Health
Researchers follow AI path to safer senolytic compounds
Senescent cell-disrupting ability of oleandrin and periplocin. be A cell survival assay to measure the senescent cell-disrupting effect in OIS. Panels show representative crystal violet staining of tissue culture dishes of confluent senescent IMR90 ER:RAS and control IMR90 ER:STOP cells cultured in 100 nM 4OHT and treated with 10 nM oleandrin, ouabain, and periplosin. increase. h. b Cell viability by quantifying the crystal violet staining of the experiment is shown in the figure. beAs described in the Methods section. Data are presented as individual data points, bars and error bars represent the mean ± SEM of 12 independent experiments. Statistical analysis was performed using one-way ANOVA (Tukey’s test) for multiple comparisons. c A cell survival assay that measures senescent cell-disrupting effects on replicative senescence. By quantification of crystal violet staining of confluent cultures of IMR90 cells at passage 27 (replicative senescence) and IMR90 cells at passage 13 (control) treated with 10 nM oleandrin, ouabain and periplosin, and DMSO as vehicle control. Graph representing cell viability. 72 hours (related to Supplementary Fig. 9b). Data are presented as individual data points, bars and error bars represent the mean ± SEM of 12 independent experiments. Statistical analysis was performed using one-way ANOVA (Tukey’s test) for multiple comparisons. d Caspase 3/7 activity assay in control IMR90 ER:STOP and senescent IMR90 ER:RAS cells cultured in medium containing 100 nM 4OHT and treated with 10 nM oleandrin, ouabain and periplosin, and DMSO as vehicle control for 35 h. . Panels show representative fluorescence images (lower panels) of caspase 3/7-positive cells and brightfield images (upper panels) of the same field for cell scoring. Percentages of green fluorescent cells for each condition are shown in panel figures. Data representative of one of two independent experiments. Scale bar represents 100 µm. ns is not important, *p < 0.05,**p< 0.01,***p < 0.001, ****p< 0.0001. Source data is provided as a source data file. credit: Nature Communications(2023). DOI: 10.1038/s41467-023-39120-1
Researchers at the University of Edinburgh in Scotland and the University of Cantabria in Spain have teamed up to develop an AI trained to discover senolytic medicinal chemistry from familiar compounds.
In the paper, “discovery of senescent cell destruction using machine learningwas published in Nature Communicationsresearchers detail their efforts to find the right chemical composition to address among more than 4,300 scientifically described compounds. cellular senescence.
Cellular senescence is a phenomenon that occurs when cells stop proliferating. This may be due to the age at which cells self-determine that they have too many accumulated mutations to replicate safely or are damaged. Senescence does not allow damaged or mutated cells to proliferate and plays an important role in limiting tumor progression.
The body can tolerate a small number of uninvolved senescent cells in its tissues. Accumulation of high levels of senescent cells with aging is associated with various forms of disease such as osteoarthritis, lung disease, Alzheimer’s disease, dementia and cancer.
of Screening method They used 58 previously identified senolytic agents and 2,465 compounds known to have no senolytic effects to train the AI. After extensive training, AI was introduced to his library of 4,340 FDA-approved or clinical-stage compounds.
The three senolytic compounds identified in this study are found in herbal medicines.in test human cells Ginggetin, periplocin, and oleandrin all three have been shown to eliminate senescent cells without damaging healthy cells.
One of the three, oleandrin, stood out from the rest as the most promising. Oleandrin is a member of the cardiac glycoside class of compounds and is often used as a heart drug. cardiac output in the meantime heart failure It can also be used to treat hypotension and arrhythmias.
The major cardiac glycoside compound in current use is ouabain, which is known to be relatively toxic and a common cause of addiction. In fact, ouabain is a key component of the poisoned darts used by Kenyan Maasai warriors.
Oleandrin exhibited superior senolytic performance to ouabain, functioning in the low nanomolar range, inhibiting its canonical target and activating the senolytic pathway with higher efficacy. Oleandrin had no effect on normal cell viability at the concentrations tested, all indicating promising senescent cell-destroying potential.
Cardiotoxicity remains a concern for oleandrin. The researchers suggest that direct application to the site of damaged tissue as a local senolytic therapy may be an effective treatment while reducing out-of-facility risks. clinical trial They are currently evaluating such topical administration of senolytic agents for osteoarthritis.
In a parallel effort, the researchers showed that extracorporeal senolytic perfusion of human transplanted livers preserved tissue architecture and regenerative capacity during cold storage.
This study used existing data to uncover previously unknown knowledge. While the actual research results provide exciting new compounds to test to combat cellular senescence, this is another example of how AI can make a valuable contribution to researchers.
For more information:
Vanessa Smer-Barreto et al., Discovery of Senescent Cell Destruction Using Machine Learning, Nature Communications(2023). DOI: 10.1038/s41467-023-39120-1
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