Investigation of quercetin and hyperoside as senolytics in adult human endothelial cells

Hwang, Hyun Tae; Tran, Darlene T.; Rebuffatti, Michelle; Li, Chin‐Shang; Knowlton, Anne A

doi:10.1371/journal.pone.0190374

Cited by 49 publications

(27 citation statements)

References 46 publications

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“…Moreover, we observed a slight but non-significant increase in proliferating cells. These findings correlate with the negative impact previously reported between the number of senescent cells and cell proliferation during IVD degeneration ( Hwang et al, 2018 ). Furthermore, culture media from control discs, showed no change in cytokine release whereas both compounds decreased levels of IL-6, IL-7, IL-8, CXCL1, CXCL6, CCL2, CCL22, GROa/b/g, IGFBP-2, TNSF-14 and OPN.…”

Section: Discussionsupporting

confidence: 91%

Senotherapeutic drugs for human intervertebral disc degeneration and low back pain

Cherif

Bisson

Mannarino

et al. 2020

eLife

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Cellular senescence is a contributor to intervertebral disc (IVD) degeneration and low back pain. Here, we found that RG-7112, a potent mouse double-minute two protein inhibitor, selectively kills senescent IVD cells through apoptosis. Gene expression pathway analysis was used to compare the functional networks of genes affected by RG-7112, a pure synthetic senolytic with o-Vanillin a natural and anti-inflammatory senolytic. Both affected a functional gene network related to cell death and survival. O-Vanillin also affected networks related to cell cycle progression as well as connective tissue development and function. Both senolytics effectively decreased the senescence-associated secretory phenotype (SASP) of IVD cells. Furthermore, bioavailability and efficacy were verified ex vivo in the physiological environment of degenerating intact human discs where a single dose improved disc matrix homeostasis. Matrix improvement correlated with a reduction in senescent cells and SASP, supporting a translational potential of targeting senescent cells as a therapeutic intervention.

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Section: Discussionsupporting

confidence: 91%

Senotherapeutic drugs for human intervertebral disc degeneration and low back pain

Cherif

Bisson

Mannarino

et al. 2020

eLife

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“…Preclinical studies in T2D identified that replicative-senescent β-cells actually contributed more to insulin production than nonsenescent cells [88], yet targeting senescent cells intermittently in mice still improved glucose tolerance and increased insulin sensitivity [89]. However, not all results are positive; in atherosclerosis, quercetin (a senolytic) was associated with nonsenescent cell death in primary human coronary artery endothelial cells [90], despite earlier studies suggesting potential benefits [91]. This suggests caution is required within this field and more trials are eagerly awaited.…”

Section: Theme 1: Accelerated Ageing In Multimorbiditymentioning

confidence: 99%

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

2020

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Multimorbidity is increasingly common and current healthcare strategies are not always aligned to treat this complex burden of disease. COPD, type-2 diabetes mellitus (T2D) and cardiovascular disease, especially atherosclerosis, occur more frequently together than expected, even when risk factors such as smoking, obesity, inactivity and poverty are considered. This supports the possibility of unifying mechanisms that contribute to the pathogenesis or progression of each condition.Neutrophilic inflammation is causally associated with COPD, and increasingly recognised in the pathogenesis of atherosclerosis and T2D, potentially forming an aetiological link between conditions. This link might reflect an overspill of inflammation from one affected organ into the systemic circulation, exposing all organs to an increased milieu of proinflammatory cytokines. Additionally, increasing evidence supports the involvement of other processes in chronic disease pathogenesis, such as cellular senescence or changes in cellular phenotypes.This review explores the current scientific evidence for inflammation, cellular ageing and cellular processes, such as reactive oxygen species production and phenotypic changes in the pathogenesis of COPD, T2D and atherosclerosis; highlighting common mechanisms shared across these diseases. We identify emerging therapeutic approaches that target these areas, but also where more work is still required to improve our understanding of the underlying cellular biology in a multimorbid disease setting.

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“…Most of the studies investigating adult human vascular endothelial function in vitro rely solely on cultured human umbilical vein endothelial cells (HUVEC). It was later reported that HUVEC obtained from the immune naïve fetal tissue shows significant variations in function compared with adult human vascular endothelium and hence may represent an inappropriate primary cell model of vascular endothelium (Hwang et al, 2018 ; O'Donnell et al, 2000 ; Tan et al, 2004 ). Therefore, to investigate the effects of RSPO3 on adult human primary macro- and micro- vascular endothelial monolayer barrier function, we employed primary endothelial cells derived from adult human coronary and pulmonary arteries, and cardiac, brain, and dermal microvascular beds, that were positively tested for vascular endothelial markers and function, and are well established as immunocompetent (Burton et al, 2011 ; Chandrasekar et al, 2004 ; Franscini et al, 2004 ; Quinlan et al, 1999 ; Skaria et al, 2017a ; Skaria et al, 2016 ; Zeuke et al, 2002 ).…”

Section: Resultsmentioning

confidence: 99%

RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1

Skaria

Bächli

Schoedon

2018

Mol Med

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BackgroundEndothelial barrier dysfunction characterized by hyperpermeability of the vascular endothelium is a key factor in the pathogenesis of chronic inflammatory diseases and affects clinical outcomes. In states of chronic inflammation, mediators secreted by activated immune cells or vascular endothelium may affect the barrier function and permeability of the vascular endothelium. The matricellular R-spondin family member RSPO3 is produced by inflammatory-activated human monocytes and vascular endothelial cells, but its effects in the regulation of vascular endothelial barrier function remains elusive.MethodsThe present study investigates the effects of RSPO3 on the barrier function of adult human primary macro- and micro- vascular endothelial monolayers. Tight monolayers of primary endothelial cells from human coronary and pulmonary arteries, and cardiac, brain, and dermal microvascular beds were treated with RSPO3 either alone or in combination with pro-inflammatory mediator IL-1β. Endothelial barrier function was assessed non-invasively in real-time using Electric Cell-substrate Impedance Sensing.ResultsRSPO3 treatment critically affected barrier function by enhancing the permeability of all vascular endothelial monolayers investigated. To confer hyperpermeable phenotype in vascular endothelial monolayers, RSPO3 induced inter-endothelial gap formation by disrupting the β-catenin and VE-cadherin alignment at adherens junctions. RSPO3 synergistically enhanced the barrier impairing properties of the pro-inflammatory mediator IL-1β.ConclusionHere, we show that the matricellular protein RSPO3 is a mediator of endothelial hyperpermeability that can act in synergy with the inflammatory mediator IL-1β. This finding stimulates further studies to delineate the endothelial barrier impairing properties of RSPO3 and its synergistic interaction with IL-1β in chronic inflammatory diseases.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0048-z) contains supplementary material, which is available to authorized users.

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Investigation of quercetin and hyperoside as senolytics in adult human endothelial cells

Cited by 49 publications

References 46 publications

Senotherapeutic drugs for human intervertebral disc degeneration and low back pain

Senotherapeutic drugs for human intervertebral disc degeneration and low back pain

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

RSPO3 impairs barrier function of human vascular endothelial monolayers and synergizes with pro-inflammatory IL-1

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