Potential senotherapeutic candidates and their combinations derived from transcriptional connectivity and network measures

Rad, Amirhossein Nayeri; Shams, Golnaz; Avelar, Roberto A.; Morowvat, Mohammad Hossein; Ghasemi, Younes

doi:10.1016/j.imu.2022.100920

Cited by 4 publications

(2 citation statements)

References 70 publications

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“…Some NRF2-activating compounds have been described as potential senotherapeutic drugs. There are two kinds of senotherapeutics: senolytics, which induce cell death (also called senolysis) of senescent cells (e.g., curcumin, quercetin, berberine), and senomorphics, which suppress pro-inflammatory senescence-associated secretory phenotypes produced by senescent cells (e.g., rapamycin, metformin, epigallocatechin gallate) [ 202 , 203 , 204 , 205 , 206 ]. A promising avenue, increasingly raised in the literature, would then be to target the senescence process.…”

Section: Nrf2 and Brain (Dys)functionsmentioning

confidence: 99%

Normal and Pathological NRF2 Signalling in the Central Nervous System

et al. 2022

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The nuclear factor erythroid 2-related factor 2 (NRF2) was originally described as a master regulator of antioxidant cellular response, but in the time since, numerous important biological functions linked to cell survival, cellular detoxification, metabolism, autophagy, proteostasis, inflammation, immunity, and differentiation have been attributed to this pleiotropic transcription factor that regulates hundreds of genes. After 40 years of in-depth research and key discoveries, NRF2 is now at the center of a vast regulatory network, revealing NRF2 signalling as increasingly complex. It is widely recognized that reactive oxygen species (ROS) play a key role in human physiological and pathological processes such as ageing, obesity, diabetes, cancer, and neurodegenerative diseases. The high oxygen consumption associated with high levels of free iron and oxidizable unsaturated lipids make the brain particularly vulnerable to oxidative stress. A good stability of NRF2 activity is thus crucial to maintain the redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, cancer, ageing, and ageing-related neurodegenerative diseases. We also discuss promising therapeutic strategies and the need for better understanding of cell-type-specific functions of NRF2 in these different fields.

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Section: Nrf2 and Brain (Dys)functionsmentioning

confidence: 99%

Normal and Pathological NRF2 Signalling in the Central Nervous System

et al. 2022

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“…However, the exact nature of senescent cells is often difficult to define, with multiple studies indicating that the most common biomarkers of senescence show different profiles across cell lines, types of senescence inducer, and the timepoint after the initial stimulus (Avelar et al, 2020; Basisty et al, 2020; Casella et al, 2019; Hernandez-Segura et al, 2017; Neri et al, 2021). This makes targeting senescent cells difficult, often requiring combinatorial approaches (Nayeri Rad et al, 2022; Saccon et al, 2021; Xu et al, 2018; Zhu et al, 2015). Although combination therapies can be increasingly effective, they also have potential to impact additional molecular networks and their off-target effects can be increasingly unpredictable.…”

Section: Introductionmentioning

confidence: 99%

Systematic transcriptomic analysis and temporal modelling of the senescent human fibroblast

Scanlan

Pease

O’Keefe

et al. 2022

Preprint

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Cell senescence is a diverse phenotype and therapies often require combinatorial approaches. Here we have systematically collected transcriptomic data related to human fibroblasts to a total of 98 studies. We formed a database describing the relevant variables for each study which we have hosted online allowing users to filter the studies to select variables and genes of interest. Our own analysis of the database revealed 13 marker genes consistently downregulated in senescent cells compared to proliferating controls; however, we also found gene expression patterns that were highly specific and reliable for different senescence inducers, cell lines, and timepoint after induction, confirming several conclusions of existing studies based on single datasets, including differences in p53 and inflammatory signals between oncogene induced senescence (OIS) and DNA damage induced senescence (DDIS). We saw little evidence of an initial TGF-β-centric SASP, but we did find evidence of a decrease in Notch signalling. Contrary to some early observations, both p16 and p21 mRNA levels appeared to rise quickly, depending on senescence type, and persist for at least 8-11 days. We concluded that while universal biomarkers of senescence are difficult to identify, the conventional senescence markers follow predictable profiles and construction of a framework for studying senescence could lead to more reproducible data.

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