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Transcriptomic profiling of human senescent cells upon treatment with the senolytic agent procyanidin C1

ABSTRACT: In the course of aging, the long term retention of senescent cells in vivo, a process mainly attributed to highly expressed BCL-family proteins, chronically damages tissues mainly through a senescence-associated secretory phenotype (SASP). It has been documented that accumulation of senescent cells accelerates aging and contributes to age-related diseases. Indeed, senescent cells can be removed by several strategies, thus preventing occurrence of chronic disorders and prolonging lifespan and healthspan. Senolytics, which eliminate senescent cells by pharmacological intervention, have recently emerged as a new line of therapeutic agents to ameliorate diverse age-related pathologies. Achieving the goal using natural or synthetic agents would have a tremendous impact on the quality of life. We report the potential of procyanidin C1 (PCC1), an epicatechin trimer natural product derived from plant sources including grape, apple, and cocoa, in targeting senescent cells via induction of apoptosis. This study demonstrates the efficacy of PCC1 in minimizing the influence of senescent cells in tissue microenvironment and provides a strong rationale for its future use in aging control and geriatric medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164012 | GEO | 2021/10/04

REPOSITORIES: GEO

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Transcriptomic profiling of human stromal cells in mouse xenografts upon treatment with chemotherapeutic drug and/or the senolytic agent procyanidin C1

Project description:Physical function declines in advanced age, portending disability, increased health expenditures, and clinical mortality. Cellular senescence leads to tissue dysfunction and contributes to the consequences of aging, but whether age-related pathologies including cancer can be alleviated by targeting senescent cells remains largely unclear. Long term retention of senescent cells in vivo, a process mainly attributed to high expression of BCL2 family proteins, causes chronical tissue damages mainly through the senescence-associated secretory phenotype (SASP). Indeed, senescent cells can be removed by several strategies, thus preventing appearance of chronic symptoms and prolonging healthspan. Strategies involving senolytics, which eliminate senescent cells by pharmacological actions, are recently emerging as a novel and prominent solution to ameliorate diverse age-related pathologies. Achieving the goal using synthetic or natural agents would generate a tremendous impact on the quality of life. We test the potential of procyanidin C1 (PCC1), a B type procyanidin flavonoid derived from plant sources including grape, apple and cocoa, in targeting senescent cells through inducing apoptosis and suppressing the pro-inflammatory phenotype. This study demonstrates the efficacy of PCC1 in restraining the SASP expression and minimizing the influence of senescent stromal cells in tumor microenvironment and provides a strong rationale for its future development in anti-aging industrial pipelines.

2021-10-04 | GSE178376 | GEO

Pure epicatechin and inflammatory gene expression profiles in circulating immune cells in (pre) hypertensive adults; a randomized double-blind, placebo-controlled, crossover trial

Project description:Introduction: There is increasing evidence that consumption of cocoa products have a beneficial effect on cardio-metabolic health, but the underlying mechanisms remain unclear. Cocoa contains a complex mixture of flavan-3-ols. Epicatechin, a major monomeric flavan-3-ol, is considered to contribute to the cardio-protective effects of cocoa. We investigated effects of pure epicatechin supplementation on whole genome gene expression profiles of circulating immune cells. Methods: In a randomized, double blind, placebo-controlled cross-over trial, 37 (pre)hypertensive (40-80y) subjects received two 4-week interventions; epicatechin (100mg/day) or placebo with a wash-out period of 4-week between both interventions. Whole genome gene expression profiles of peripheral blood mononuclear cells were determined before and after both interventions. Results: After epicatechin supplementation 1180 genes were significantly regulated, of which 234 were also significantly regulated compared to placebo. Epicatechin supplementation up-regulated gene sets involved in transcription/translation and tubulin folding and down-regulated gene sets involved in inflammation. Only a few genes within these regulated gene sets were actually significantly changed upon epicatechin supplementation. Upstream regulators that were shown to be inhibited were classified as cytokine or inflammatory type molecules. Conclusion: Pure epicatechin supplementation modestly reduced gene expression related to inflammation signalling routes in circulating immune cells. These routes are known to play a role in cardiovascular health

2018-04-25 | GSE84453 | GEO

Nintedanib induces senolytic effect via STAT3 inhibition

Project description:Selective removal of senescent cells, or the concept of senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced cell death in primary human diploid fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without cytotoxicity. Interestingly, compared with ABT263, nintedanib showed a different mode of activating caspase-9 in the intrinsic apoptotic pathway, in that nintedanib did not suppress the levels of Bcl-2 family proteins in senescent cells. In more detail, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused drug-induced cell death in senescent cells. STAT3 knockdown in senescent cells also induced caspase activation. Moreover, nintedanib reduced the number of senescent cells stained based on senescence-associated β-galactosidase activity and airway resistance in a mouse model of bleomycin-induced lung fibrosis. Overall, we identified that nintedanib could be used as a new senolytic agent and that inhibiting STAT3 could be a potential approach for inducing selective cell death in senescent cells. Our findings will pave the way for expanding senolytic toolkits in response to various aging statuses and age-related diseases.

2022-09-06 | GSE210020 | GEO

Effect of Epicatechin on LPS-induced MAC-T cells by proteomics

Project description:Mastitis, a most common disease affecting dairy cows worldwide, causes great economic losses to the dairy industry. And, Epicatechin belongs to natural polyphenols, which are abundant in cocoa, grapes, tea and many other fruits and vegetables. We sought to identify Epicatechin-regulated on MAC-T cells by proteomics.

2021-03-31 | PXD025116 |

Transcriptomic profiling of senescent human stromal cells upon medicinal intervention with rutin

Project description:Aging and age-related pathologies can be delayed by specifically targeting the senescence-associated secretory phenotype (SASP), a hallmark feature of senescent cells. Achieving the goal using natural or synthetic agents would have a tremendous impact on the quality of lifespan and burden of age-related chronic diseases. We report the potential of rutin, a bioactive phytochemical component derived from natural plants specifically ginkgo boliva, in targeting senescent cells via suppression of the SASP. This study demonstrates the efficacy of rutin as medicinal agent in controlling the influence of senescent human stromal cells and provides a strong rationale for its future use in aging intervention and geriatric medicine.

2023-11-02 | GSE190279 | GEO

Epicatechin metabolites exert epigenetic regulation in endothelial cells by modulating DNA methylation profile

Project description:Diets rich in flavanols are known to exert beneficial cardiovascular health effects. We previously showed that epicatechin metabolites reduce monocyte-endothelial cell adhesion by modulating expression of genes in HUVECs involved in cell adhesion signaling pathways. The aim of the present study is to examine potential epigenetic remodeling of HUVEC cells upon inflammation in presence or absence of cocoa derived epicatechin metabolites through genomewide DNA methylation profiling. Epicatechin metabolites were found to trigger DNA hypermethylation in gene bodies and intergenic genomic regions, while hypomethylation in promoter regions. In addition, pathway enrichment of differentially methylated genes demonstrates epigenetic remodeling cell adhesion and cytoskeleton signaling pathways. Finally, in silico docking supports evidence for direct regulation of DNMTs through epicatechin binding. In conclusion, our study provides evidence that epicatechin metabolites elicit vascular health effects in part through epigenetic regulation of endothelial cell adhesion functions.

2019-12-31 | GSE133418 | GEO

Chemo-senolytic therapeutic potential against angiosarcoma

Project description:Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype (SASP) genes are activated in senescent angiosarcoma cells and that ABT-263 treatment eliminates senescent cells expressing genes in the type-I interferon (IFN-I) pathway. Moreover, we show that cisplatin treatment alone requires a high dose to remove angiosarcoma cells, whereas a lower dose of cisplatin is sufficient to induce senescence, followed by the elimination of senescent cells by senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.

2024-03-23 | GSE245935 | GEO

Transcriptomic profiling of human senescent cells upon treatment with the senolytic agent procyanidin C1

Project description:Transcriptomic profiling of human senescent cells upon treatment with the senolytic agent procyanidin C1

| PRJNA688509 | ENA

Prophilactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Project description:Senescent cells accumulate in organisms over time as a result of tissue damage and impaired immune surveillance and are thought to contribute to age-related tissue decline1,2. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness3-7. While small-molecule drugs capable of eliminating senescent cells (known as ‘senolytics’) partially replicate these phenotypes, many have uncertain mechanisms of action and all require continuous administration to be effective. As an alternative approach, we previously developed a cell-based senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting uPAR, a cell-surface protein upregulated on senescent cells, and showed these can safely and efficiently eliminate senescent cells in young animals and reverse liver fibrosis8. We now show that uPAR-positive senescent cells accumulate during physiological aging and that they can be safely targeted with senolytic CAR T cells in aged animals. Treatment with anti uPAR CAR T cells ameliorates metabolic dysfunction by improving glucose tolerance and exercise capacity in physiological aging as well as in a model of metabolic syndrome. Importantly, the beneficial effects of senolytic CAR T cells are long lasting; single administration of a low dose is sufficient to achieve long-term therapeutic and preventive effects.

2023-12-08 | GSE243616 | GEO

Senolytic treatment alleviates doxorubicin-induced chemobrain

Project description:Doxorubicin (Dox) is a widely used treatment for cancer, which can result in chemotherapy induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging, since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves induction of peripheral cellular senescence and the release ofsenescence-associated secretory phenotype (SASP) factors, which enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT-263, which also has limited access to the brain. While Dox treatment influenced several measures linked to aging, including peripheral inflammation, morphological measure of microglial activation, cognition, and synaptic function,the effects of Dox treatment on brain (i.e. dentate gyrus) gene expression did not approximate aging to the same degree as other measures.Regardless, ABT-263 prevent or limited most of the Dox induced effects, including brain gene expression. The resultsemphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate thatdifferences between aging and Dox treatment on brain gene expression are important in considering Dox treatment as a model of aging.

2024-02-26 | GSE236404 | GEO

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