A High Content Drug Screen Identifies Ursolic Acid as an Inhibitor of Amyloid β Protein Interactions with Its Receptor CD36

Wilkinson, Kim; Boyd, Justin D.; Glicksman, Marcie A.; Moore, Kathryn J.; Khoury, Joseph El

doi:10.1074/jbc.m111.232116

Cited by 86 publications

(71 citation statements)

References 24 publications

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“…Ursolic acid (UA) has been previously described and characterized by a cell-based assay as an inhibitor of CD36-Aβ interaction 11 . These authors demonstrated also that this compound inhibits the production of ROS induced by Aβ in N9 microglia cells.…”

Section: Resultsmentioning

confidence: 99%

“…CD36 receptor has been identified as essential in the Aβ-induced microglia activation and several studies point it out as a suitable target for drug development 7, 25 . Engagement of Aβ to CD36 leads to the secretion of TNF-α, IL-1β, MCP-1, among other proinflammatory mediators 6, 7 and the inhibition of this interaction impair the response of cells to Aβ 61113 . However, current immunotherapy options for AD are not yet considering modulators of the Aβ-CD36 interaction to block or reduce the subsequent inflammatory reaction.…”

Section: Discussionmentioning

confidence: 99%

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Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Doens

Valiente

Mfuh³

et al. 2017

ACS Chem. Neurosci.

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Neuroinflammation is one of the hallmarks of Alzheimer's disease pathology. Amyloid β has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid β by microglia depends on the expression of several receptors implicated in the clearance of amyloid and in cell activation. CD36 receptor expressed on microglia interacts with fibrils of amyloid inducing the release of pro-inflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid β compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid β to CD36. We have found 7 molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid β. Molecular docking simulations have suggested the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as a target of these compounds. These molecules also inhibited the production of TNF-α, IL-6 and IL-1β by peritoneal macrophages stimulated with fibrils of amyloid β. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Doens

Valiente

Mfuh³

et al. 2017

ACS Chem. Neurosci.

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“…It has been used for pharmaceutical, cosmetic and food preparations. Of note, ursolic acid has garnered much attention as a therapeutic compound in a number of diseases, such as cancer (9), diabetes (10), Alzheimer's disease (11) and obesity (12), due to its anti-inflamThe combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway matory and antitumor properties. Moreover, this triterpene has been reported to increase the insulin-induced phosphorylation of Akt, a serine/threonine-specific protein kinase, that plays a key role in multiple cellular processes, such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration (13).…”

Section: Introductionmentioning

confidence: 99%

The combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway

Kim

Sung

Kang

et al. 2014

International Journal of Molecular Medicine

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Abstract. Aging causes phenotypic changes in skeletal muscle progenitor cells that lead to the progressive loss of myogenic differentiation and thus a decrease in muscle mass. The naturally occurring triterpene, ursolic acid, has been reported to be an effective agent for the prevention of muscle loss by suppressing degenerative muscular dystrophy. Leucine, a branched-chain amino acid, and its metabolite, β-hydroxy-β-methylbutyric acid, have been reported to enhance protein synthesis in skeletal muscle. Therefore, the aim of the present study was to investigate whether the combination of ursolic acid and leucine promotes greater myogenic differentiation compared to either agent alone in C2C12 murine myoblasts. Morphological changes were observed and creatine kinase (CK) activity analysis was performed to determine the conditions through which the combination of ursolic acid and leucine would exert the most prominent effects on muscle cell differentiation. The effect of the combination of ursolic acid and leucine on the expression of myogenic differentiation marker genes was examined by RT-PCR and western blot analysis. The combination of ursolic acid (0.5 µM) and leucine (10 µM) proved to be the most effective in promoting myogenic differentiation. The combination of ursolic acid and leucine significantly increased CK activity than treatment with either agent alone. The level of myosin heavy chain, a myogenic differentiation marker protein, was also enhanced by the combination of ursolic acid and leucine. The combination of ursolic acid and leucine significantly induced the expression of myogenic differentiation marker genes, such as myogenic differentiation 1 (MyoD) and myogenin, at both the mRNA and protein level. In addition, the number of myotubes and the fusion index were increased. These findings indicate that the combination of ursolic acid and leucine promotes muscle cell differentiation, thus suggesting that this combination of agents may prove to be beneficial in increasing muscle mass.

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“…Ursane-type and oleanane-type pentacyclic triterpenes (C30 compounds) are known for a variety of pharmaceutical properties, including anti-inflammatory, hepatoprotective, antitumor, antihyperlipidemic, antiulcer, and antimicrobial benefits (Kunkel et al, 2011;Wilkinson et al, 2011;Kurek et al, 2012;da Silva Ferreira et al, 2013;Kong et al, 2013). However, there are limited data on the biosynthesis of these secondary metabolites in plants (Brendolise et al, 2011;Huang et al, 2012;Yu et al, 2013).…”

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confidence: 99%

Methyl Jasmonate-Elicited Transcriptional Responses and Pentacyclic Triterpene Biosynthesis in Sweet Basil

et al. 2013

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Sweet basil (Ocimum basilicum) is well known for its diverse pharmacological properties and has been widely used in traditional medicine for the treatment of various ailments. Although a variety of secondary metabolites with potent biological activities are identified, our understanding of the biosynthetic pathways that produce them has remained largely incomplete. We studied transcriptional changes in sweet basil after methyl jasmonate (MeJA) treatment, which is considered an elicitor of secondary metabolites, and identified 388 candidate MeJA-responsive unique transcripts. Transcript analysis suggests that in addition to controlling its own biosynthesis and stress responses, MeJA up-regulates transcripts of the various secondary metabolic pathways, including terpenoids and phenylpropanoids/flavonoids. Furthermore, combined transcript and metabolite analysis revealed MeJA-induced biosynthesis of the medicinally important ursane-type and oleanane-type pentacyclic triterpenes. Two MeJAresponsive oxidosqualene cyclases (ObAS1 and ObAS2) that encode for 761-and 765-amino acid proteins, respectively, were identified and characterized. Functional expressions of ObAS1 and ObAS2 in Saccharomyces cerevisiae led to the production of b-amyrin and a-amyrin, the direct precursors of oleanane-type and ursane-type pentacyclic triterpenes, respectively. ObAS1 was identified as a b-amyrin synthase, whereas ObAS2 was a mixed amyrin synthase that produced both a-amyrin and b-amyrin but had a product preference for a-amyrin. Moreover, transcript and metabolite analysis shed light on the spatiotemporal regulation of pentacyclic triterpene biosynthesis in sweet basil. Taken together, these results will be helpful in elucidating the secondary metabolic pathways of sweet basil and developing metabolic engineering strategies for enhanced production of pentacyclic triterpenes.

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A High Content Drug Screen Identifies Ursolic Acid as an Inhibitor of Amyloid β Protein Interactions with Its Receptor CD36

Cited by 86 publications

References 24 publications

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer’s Disease

The combination of ursolic acid and leucine potentiates the differentiation of C2C12 murine myoblasts through the mTOR signaling pathway

Methyl Jasmonate-Elicited Transcriptional Responses and Pentacyclic Triterpene Biosynthesis in Sweet Basil

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