Could PCSK9 be a new therapeutic target of Eugenol? In vitro and in silico evaluation of hypothesis

Zia, Saadiya; Batool, Sidra; Shahid, Ramla

doi:10.1016/j.mehy.2019.109513

Cited by 15 publications

(8 citation statements)

References 36 publications

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“…Particularly, ChIP-qPCR showed that the enrichment of H3 acetylation on the promoters of lipid metabolism genes including APOC1, P2RX1, PCSK9, and LPPR3 was decreased (Figure 4B). These genes as key downstream targets of ANP32A showed relatively high expression levels in leukemia patients compared with that in healthy donors [12,18]. Consistently, the expression of these genes was downregulated upon H3BP-GFP expression in comparison with the GFP control expression (Figure 4C) while no alteration of these genes was observed without doxycycline treatment (Supplementary Figure 1).…”

Section: Resultssupporting

confidence: 54%

Small Peptide Targeting ANP32A as a Novel Strategy For Acute Myeloid Leukemia Therapy

Wang

Guo

Zhang

et al. 2021

Preprint

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Background: Clinic therapy of acute myeloid leukemia (AML) remains unsatisfactory that urges for development of novel strategy. Recent studies identified ANP32A as a novel biomarker of unfavorable outcome of leukemia, which promoted leukemogenesis by increasing H3 acetylation and the expression of lipid metabolism genes. It is of great significance to investigate whether targeting ANP32A is a novel strategy for leukemia therapy. Results: To target ANP32A, we identified a peptide that competed with ANP32A to bind to histone 3 (termed as H3-binding peptide, H3BP). Disrupting ANP32A and H3 interaction by the overexpression of H3BP-GFP fusion protein mimicked the effect of ANP32A knockdown, impaired H3 acetylation on multiple locus of target genes, reduced proliferation, and caused apoptosis in leukemia cells. Furthermore, a synthesized membrane-penetrating peptide TAT-H3BP effectively entered into leukemia cells and reproduced such effect. In vivo, TAT-H3BP showed potent efficacy against leukemia: Intra-tumor injection of TAT-H3BP significantly reduced the volume of subcutaneous tumors in nude mice and recipient mice engrafted with TAT-H3BP-pretreated 6133/MPL W515L cells exhibited ameliorated leukemia burden and prolonged survival. Noticeably, TAT-H3BP efficiently suppressed proliferation and colony-forming unit of human primary AML cells without affecting normal cord blood cells.Conclusions: Intervening the physical interaction of ANP32A with H3 impairs the oncogenicity of ANP32A and may be a promising therapeutic strategy against AML.

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Section: Resultssupporting

confidence: 54%

Small Peptide Targeting ANP32A as a Novel Strategy For Acute Myeloid Leukemia Therapy

Wang

Guo

Zhang

et al. 2021

Preprint

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“…4 C ). These genes as key downstream targets of ANP32A showed relatively high expression levels in AML patients compared with that in healthy donors [ 8 , 22 ]. Consistently, the expression of these genes was downregulated upon H3BP-GFP expression in comparison with the GFP expression ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Small peptide targeting ANP32A as a novel strategy for acute myeloid leukemia therapy

Wang

Guo

Zhang

et al. 2022

Translational Oncology

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Highlights H3BP targeted ANP32A against AML by competitively disrupting ANP32A and H3 interaction and decreasing H3 acetylation and the expression of lipid metabolism genes. Expressed H3BP-GFP and synthetic TAT-H3BP peptide impaired H3 acetylation on multiple locus of target genes that reduced proliferation and caused apoptosis of leukemia cells in vitro . TAT-H3BP exhibits potent efficacy against leukemia in vivo : Intra-tumor injection of TAT-H3BP peptide prominently diminished the volume of subcutaneous tumors in nude mice; AMKL mice engrafted with TAT-H3BP-pretreated 6133/MPL W515L cells displayed dramatically moderated disease burden and prolonged survival time. TAT-H3BP peptide possess a therapeutic potential in patients with AML for micromole concentration of TAT-H3BP peptide efficiently inhibited the proliferation and CFU of human primary leukemia cells from AML patients. High ANP32A levels in human primary AML cells correlate with the intervention effect of TAT-H3BP peptide.

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“…More recently, a molecular docking analysis revealed hydrophobic interactions between ligand eugenol and PCSK9 (Figure 1) [117]. In addition, eugenol was found to reduce the expression of PCSK9 in Jurkat cells [117]. This effect can be the result of a physical interaction between the two molecules, or an indirect inhibitory effect of eugenol on the SREBP pathway ( Figure 1) [115].…”

Section: Eugenolmentioning

confidence: 97%

“…Animal studies have shown that eugenol lowers serum cholesterol levels and inhibits lipogenesis in the liver, thus suggesting a protective effect on atherosclerosis and fatty liver disease [115,116]. More recently, a molecular docking analysis revealed hydrophobic interactions between ligand eugenol and PCSK9 (Figure 1) [117]. In addition, eugenol was found to reduce the expression of PCSK9 in Jurkat cells [117].…”

Section: Eugenolmentioning

confidence: 99%

Naturally Occurring PCSK9 Inhibitors

et al. 2020

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Genetic, epidemiological and pharmacological data have led to the conclusion that antagonizing or inhibiting Proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular events. This clinical outcome is mainly related to the pivotal role of PCSK9 in controlling low-density lipoprotein (LDL) cholesterol levels. The absence of oral and affordable anti-PCSK9 medications has limited the beneficial effects of this new therapeutic option. A possible breakthrough in this field may come from the discovery of new naturally occurring PCSK9 inhibitors as a starting point for the development of oral, small molecules, to be used in combination with statins in order to increase the percentage of patients reaching their LDL-cholesterol target levels. In the present review, we have summarized the current knowledge on natural compounds or extracts that have shown an inhibitory effect on PCSK9, either in experimental or clinical settings. When available, the pharmacodynamic and pharmacokinetic profiles of the listed compounds are described.

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Could PCSK9 be a new therapeutic target of Eugenol? In vitro and in silico evaluation of hypothesis

Cited by 15 publications

References 36 publications

Small Peptide Targeting ANP32A as a Novel Strategy For Acute Myeloid Leukemia Therapy

Small Peptide Targeting ANP32A as a Novel Strategy For Acute Myeloid Leukemia Therapy

Small peptide targeting ANP32A as a novel strategy for acute myeloid leukemia therapy

Naturally Occurring PCSK9 Inhibitors

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