New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463

Zhu, Yi; Doornebal, Ewald J.; Pirtskhalava, Tamar; Giorgadze, Nino; Wentworth, Mark; Fuhrmann-Stroissnigg, Heike; Niedernhofer, Laura J.; Robbins, Paul D.; Tchkonia, Tamar; Kirkland, James L.

doi:10.18632/aging.101202

Cited by 555 publications

(418 citation statements)

References 36 publications

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“…Probably the molecular regulatory mechanism of quercetin is cell type specific, which also explains why quercetin has beneficial function in a wide range of organs and tissues . Recent study has proposed quercetin carries senolytic potential . Senolytic compounds refer to the class of molecules that can specifically eliminate senescent cells in the tissue.…”

Section: Discussionmentioning

confidence: 99%

Topical application of quercetin improves wound healing in pressure ulcer lesions

Yin

Wang

2018

Experimental Dermatology

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The ischaemia-reperfusion (I/R)-induced skin lesion has been identified as primary cause of pressure ulcers. To date, attempts to prevent pressure ulcers have not produced a significant improvement. Quercetin, one of the most widely distributed flavonoids in fruits and vegetables, exhibits its antioxidant and anti-inflammatory properties against many diseases, including ischaemic heart disease, atherosclerosis and renal injury. In vitro wound scratch assay was first used to assess the function of quercetin in wounding cell model. Next, animal pressure ulcers model was established with two cycles of I/R. The impact of quercetin in the wound recovery, immune cell infiltration and pro-inflammatory cytokines production was investigated in this model. Mechanistic regulation of quercetin at the wound site was also studied. Quercetin accelerated wound closure in cell scratch assay. Dose-response study suggested 1 μmol/L quercetin for in vivo study. In I/R injury model, quercetin treatment significantly accelerated wound closure, reduced immune cell infiltration and pro-inflammatory cytokines production. Signalling study showed quercetin treatment inhibited MAPK but not NFĸB activation. Quercetin treatment improved the wound healing process in I/R lesions by suppressing MAPK pathway. Our results supported that quercetin could be a potential therapeutic agent for pressure ulcers.

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Section: Discussionmentioning

confidence: 99%

Topical application of quercetin improves wound healing in pressure ulcer lesions

Yin

Wang

2018

Experimental Dermatology

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“…A few so called 'senolytics' have been identified, which primarily tar get the apoptosis regulator Bcl 2 prosurvival pathway. These senolytics include the combination of dasatinib and quercetin 160 , the quercetin related flavonoid fise tin 189 , and the small molecule navitoclax 190,191 . In addi tion, an artificial peptide, made up of d amino acids (as opposed to l amino acids, which are used by cells for protein synthesis) representing the reversed order of the forkhead box protein O4 (FOXO4) interaction domain with p53, was reported to promote apoptosis in senescent cells and to counteract ageing effects in mice by interference with FOXO4-p53 interaction 192 .…”

Section: Pharmacological Modulation Of Pqcmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…However, both ABT‐263 and ABT‐737 are toxic for neutrophils and platelets (Cang et al , ), which may limit their clinical development. Second‐generation inhibitors of the BCL‐2 family of proteins include the BCL‐xL inhibitors A1331852 and A1155463, which induced selective apoptosis of senescent HUVEC and IMR90 cells, but not of senescent human preadipocytes (Zhu et al , ). Preadipocytes appear resistant to BCL2 family member blockade, suggesting heterogeneity in cell‐intrinsic senescence pathways (Zhu et al , ).…”

Section: Introductionmentioning

confidence: 99%

Targeting senescent cells in translational medicine

et al. 2019

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Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs during ageing, contribute to tissue dysfunction and give rise to pathological manifestations. Senescence is therefore a defining feature of a variety of human age‐related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. In addition, in vivo identification of senescent cells has significant potential for early diagnosis of multiple pathologies. Here, we review existing senolytics, small molecules and drug delivery tools used in preclinical therapeutic strategies involving cellular senescence, as well as probes to trace senescent cells. We also review the clinical research landscape in senescence and discuss how identifying and targeting cellular senescence might positively affect pathological and ageing processes.

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New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463

Cited by 555 publications

References 36 publications

Topical application of quercetin improves wound healing in pressure ulcer lesions

Topical application of quercetin improves wound healing in pressure ulcer lesions

Proteostasis in cardiac health and disease

Targeting senescent cells in translational medicine

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