ABSTRACT
BACKGROUND: The clivus forms the central skull base between the dorsum sellae and the foramen magnum. Although bony variations of the inferior surface of the clivus are well-recognized and have been well studied, studies of bony variations of the basilar (superior) surface of the clivus are scarce. Therefore, the present study was performed to investigate bony anatomical variations on the basilar part of the clivus. METHODS: Computed tomography scans belonging to 407 Indian subjects from the CQ500 open-access dataset were retrospectively reviewed. RESULTS: Bony tubercles on the basilar surface of the clivus were found in 40 cases (9.83%). They were classified into three types including single, double and triple. A single tubercle was found in 35 cases (8.60%) including 12 on the left (2.95%), 10 on the right (2.46%) and 13 in the center (3.19%). The tubercles were doubled in four cases (0.98%) and tripled in one case (0.25%). The average width and height of the tubercles were 4.4 ± 1.5 mm (range 1.4-7.9 mm) and 1.7 ± 0.7 mm (range 0.8-4.2 mm), respectively. Ninety-five (95%) percent of the tubercles were located on the lower half of the clivus. CONCLUSIONS: To our knowledge, these tubercles have not been previously described. Therefore, we suggest the terms "basilar tubercles of the clivus" and "basilar eminences of the clivus", depending on their sizes. Knowledge of these newly described structures is important when interpreting radiological images of the skull base.
Subject(s)
Cranial Fossa, Posterior , Skull Base , Humans , Retrospective Studies , Cranial Fossa, Posterior/diagnostic imaging , Skull Base/diagnostic imaging , Foramen Magnum/diagnostic imaging , Tomography, X-Ray ComputedABSTRACT
The pathological finding of amyloid-ß (Aß) 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 Aß 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 Aß 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 Aß 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 Aß aggregate, thus attenuating its toxicity. In conclusion, 2-BTHF from H. scabra could protect C. elegans from Aß toxicity by suppressing its aggregation via an HSF-1-regulated autophagic pathway and has been implicated as a potential drug for AD.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/antagonists & inhibitors , Furans/pharmacology , Holothuria/chemistry , Neuroprotective Agents/pharmacology , Paralysis/prevention & control , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Animals , Animals, Genetically Modified , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Binding Sites , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/antagonists & inhibitors , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Disease Models, Animal , Furans/chemistry , Furans/isolation & purification , Gene Expression Regulation , Humans , Molecular Docking Simulation , Neuroprotective Agents/chemistry , Neuroprotective Agents/isolation & purification , Paralysis/genetics , Paralysis/metabolism , Paralysis/pathology , Protein Aggregates/drug effects , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Oligomeric assembly of Amyloid-ß (Aß) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of Aß oligomers could halt the disease progression. In this study, by using transgenic Caenorhabditis elegans model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber Cucumaria frondosa saponin with anti-cancer activity, on Aß aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 µM significantly delayed the worm paralysis caused by Aß aggregation as compared with control group. In addition, the number of Aß plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of Aß species in the transgenic C. elegans were significantly reduced upon treatment with frondoside A, whereas the level of Aß monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of Aß. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express Aß. Taken together, these data suggested that low dose of frondoside A could protect against Aß-induced toxicity by primarily suppressing the formation of Aß oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-Aß aggregation should be studied and elucidated in the future.
