Objective: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because... Show moreObjective: Intraplaque neovascularization is an important feature of unstable human atherosclerotic plaques. However, its impact on plaque formation and stability is poorly studied. Because proliferating endothelial cells generate up to 85% of their ATP from glycolysis, we investigated whether pharmacological inhibition of glycolytic flux by the small-molecule 3PO (3-[3-pyridinyl]-1-[4-pyridinyl]-2-propen-1-one) could have beneficial effects on plaque formation and composition. Approach and Results: ApoE-/- (apolipoprotein E deficient) mice treated with 3PO (50 µg/g, ip; 4×/wk, 4 weeks) showed a metabolic switch toward ketone body formation. Treatment of ApoE-/-Fbn1C1039G+/- mice with 3PO (50 µg/g, ip) either after 4 (preventive, twice/wk, 10 weeks) or 16 weeks of Western diet (curative, 4×/wk, 4 weeks) inhibited intraplaque neovascularization by 50% and 38%, respectively. Plaque formation was significantly reduced in all 3PO-treated animals. This effect was independent of intraplaque neovascularization. In vitro experiments showed that 3PO favors an anti-inflammatory M2 macrophage subtype and suppresses an M1 proinflammatory phenotype. Moreover, 3PO induced autophagy, which in turn impaired NF-κB (nuclear factor-kappa B) signaling and inhibited TNF-α (tumor necrosis factor-alpha)-mediated VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) upregulation. Consistently, a preventive 3PO regimen reduced endothelial VCAM-1 expression in vivo. Furthermore, 3PO improved cardiac function in ApoE-/-Fbn1C1039G+/- mice after 10 weeks of treatment.Conclusions: Partial inhibition of glycolysis restrained intraplaque angiogenesis without affecting plaque composition. However, less plaques were formed, which was accompanied by downregulation of endothelial adhesion molecules-an event that depends on autophagy induction. Inhibition of coronary plaque formation by 3PO resulted in an overall improved cardiac function. Show less
Stuivenga, M.; Giltay, E.J.; Cools, O.; Roosens, L.; Neels, H.; Sabbe, B. 2019
ABSTRACTIntroduction: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantlycontribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor... Show moreABSTRACTIntroduction: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantlycontribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been furtherinvestigated for GAD.Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone andprovides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxietydisorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the CochraneLibrary.Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However,vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclearwhether the drug’s dual mechanism of action provides greater efficacy than prevailing treatmentoptions. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety inlarger and more diverse populations. Although vilazodone may have an additional advantage for thetreatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacyover and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodoneshould be considered as a second- or third-line treatment option for MDD and GAD. Show less