Senolytics - Revision history

Dmitry Dzhagarov: /* Senescent cells as a factor of aging and age-associated diseases */

2024-08-24T15:28:24Z

Senescent cells as a factor of aging and age-associated diseases

← Older revision		Revision as of 15:28, 24 August 2024
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	Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP\|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>		Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP\|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

	Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.		Multicellular organisms usually contain tissue-resident stem and progenitor cells that consistently give rise to new cells for tissue building and regeneration.<ref>DiLoreto, R., & Murphy, C. T. (2015). The cell biology of aging. Molecular biology of the cell, 26(25), 4524-4531. PMID: 26668170 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678010 link] DOI: 10.1091/mbc.E14-06-1084</ref> However, in order for new cells to take their place, it is necessary to first remove the old ones that have lost their effectiveness. While the body is young, it easily removes senescent cells with the help of the immune system<ref name="zombies"/><ref name="immune">Yousefzadeh, M. J., Flores, R. R., Zhu, Y. I., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., ... & Niedernhofer, L. J. (2021). An aged immune system drives senescence and ageing of solid organs. Nature, 594(7861), 100-105. PMID: 33981041 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684299 link] DOI: 10.1038/s41586-021-03547-7</ref><ref>Muñoz-Espín, D., & Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews Molecular cell biology, 15(7), 482-496. PMID: 24954210 DOI:[https://doi.org/10.1038/nrm3823 link]</ref> and '''by selecting the fittest cells with the help of [[Cell Competition]]''',<ref>Maruyama, T., & Fujita, Y. (2022). Cell competition in vertebrates—a key machinery for tissue homeostasis. Current Opinion in Genetics & Development, 72, 15-21. PMID: 34634592 DOI:[https://doi.org/10.1016/j.gde.2021.09.006 link]</ref><ref name="compet"/><ref>Merino, M. M. (2023). Azot expression in the Drosophila gut modulates organismal lifespan. Communicative & Integrative Biology, 16(1), 2156735. PMID: 36606245 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809965 link] DOI: 10.1080/19420889.2022.2156735</ref><ref>Yusupova, M., & Fuchs, Y. (2023). To not love thy neighbor: mechanisms of cell competition in stem cells and beyond. Cell Death & Differentiation, 30(4), 979-991. PMID: 36813919 PMCID: PMC10070350 (available on 2024-04-01) DOI:[https://doi.org/10.1038/s41418-023-01114-3 10.1038/s41418-023-01114-3]</ref> maintaining tissue and organ health.<ref>Yusupova, M., Ankawa, R., Yosefzon, Y., Meiri, D., Bachelet, I., & Fuchs, Y. (2023). Apoptotic dysregulation mediates stem cell competition and tissue regeneration. Nature Communications, 14(1), 7547. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10662150/ PMC10662150] PMID:37985759 DOI:10.1038/s41467-023-41684-x</ref>

	==== Markers of cellular senescence ====		==== Markers of cellular senescence ====

Dmitry Dzhagarov: /* Senolytic CAR T cells */

2024-07-28T12:38:42Z

Senolytic CAR T cells

← Older revision		Revision as of 12:38, 28 July 2024
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	and improved physical and heart function. Spontaneous tumor burden in these mice was reduced.<ref>Garcia H. et al., & Lewis J.D. (2023). SYSTEMIC SENOLYSIS USING A GENETIC MEDICINE IMPROVES HEALTHSPAN IN NATURALLY AGED MICE. Abstracts of 13TH INTERNATIONAL CONFERENCE ON FRAILTY & SARCOPENIA RESEARCH (ICFSR)</ref>		and improved physical and heart function. Spontaneous tumor burden in these mice was reduced.<ref>Garcia H. et al., & Lewis J.D. (2023). SYSTEMIC SENOLYSIS USING A GENETIC MEDICINE IMPROVES HEALTHSPAN IN NATURALLY AGED MICE. Abstracts of 13TH INTERNATIONAL CONFERENCE ON FRAILTY & SARCOPENIA RESEARCH (ICFSR)</ref>

	==== Senolytic CAR T cells ====		==== Senolytic CAR T cells and natural killer (NK) cells ====
	Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/><ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>		Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/><ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>
	Diminished Natural killer (NK) cells activity in elderly individuals is associated with disorders such as atherosclerosis, the development of hypertension<ref>Lee, Y. K., Suh, E., Oh, H., Haam, J. H., & Kim, Y. S. (2024). Decreased natural killer cell activity as a potential predictor of hypertensive incidence. Frontiers in Immunology, 15, 1376421. PMID: 38715619 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074345/ PMC11074345] DOI: 10.3389/fimmu.2024.1376421</ref> and an elevated risk of mortality.<ref>Cho, A. R., Suh, E., Oh, H., Cho, B. H., Gil, M., & Lee, Y. K. (2023). Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study. International Journal of Molecular Sciences, 24(15), 12505. PMID: 37569879 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10419953/ PMC10419953] DOI: 10.3390/ijms241512505</ref><ref>Ogata, K., Yokose, N., Tamura, H., An, E., Nakamura, K., Dan, K., & Nomura, T. (1997). Natural killer cells in the late decades of human life. Clinical Immunology and Immunopathology, 84(3), 269-275. PMID: 9281385 DOI: 10.1006/clin.1997.4401</ref><ref>Ogata, K., An, E., Shioi, Y., Nakamura, K., Luo, S., Yokose, N., ... & Dan, K. (2001). Association between natural killer cell activity and infection in immunologically normal elderly people. Clinical & Experimental Immunology, 124(3), 392-397. PMID: 11472399 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906081/ PMC1906081] DOI: 10.1046/j.1365-2249.2001.01571.x</ref>		Diminished Natural killer (NK) cells activity in elderly individuals is associated with disorders such as atherosclerosis, the development of hypertension<ref>Delaney, J. A., Olson, N. C., Sitlani, C. M., Fohner, A. E., Huber, S. A., Landay, A. L., ... & Doyle, M. F. (2021). Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA). BMC Cardiovascular Disorders, 21, 1-9. PMID: 33482725 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821496/ PMC7821496] DOI: 10.1186/s12872-021-01857-2</ref><ref>Lee, Y. K., Suh, E., Oh, H., Haam, J. H., & Kim, Y. S. (2024). Decreased natural killer cell activity as a potential predictor of hypertensive incidence. Frontiers in Immunology, 15, 1376421. PMID: 38715619 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074345/ PMC11074345] DOI: 10.3389/fimmu.2024.1376421</ref> and an elevated risk of mortality.<ref>Cho, A. R., Suh, E., Oh, H., Cho, B. H., Gil, M., & Lee, Y. K. (2023). Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study. International Journal of Molecular Sciences, 24(15), 12505. PMID: 37569879 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10419953/ PMC10419953] DOI: 10.3390/ijms241512505</ref><ref>Ogata, K., Yokose, N., Tamura, H., An, E., Nakamura, K., Dan, K., & Nomura, T. (1997). Natural killer cells in the late decades of human life. Clinical Immunology and Immunopathology, 84(3), 269-275. PMID: 9281385 DOI: 10.1006/clin.1997.4401</ref><ref>Ogata, K., An, E., Shioi, Y., Nakamura, K., Luo, S., Yokose, N., ... & Dan, K. (2001). Association between natural killer cell activity and infection in immunologically normal elderly people. Clinical & Experimental Immunology, 124(3), 392-397. PMID: 11472399 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906081/ PMC1906081] DOI: 10.1046/j.1365-2249.2001.01571.x</ref>

	Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref name="uPAR" >Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 PMC7426266] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.		Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref name="uPAR" >Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 PMC7426266] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
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	Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>		Barriers to using this technology in the clinic are that clinical production of CAR-T cells is still complex, expensive and time-consuming, and because of adverse effects such as cytokine release syndrome (CRS), caused by the massive release of proinflammatory cytokines by activated T cells and other immune cells. In addition, exogenously produced CAR-T cells are usually short-lived after repeated injections into the recipient.<ref>Friedman, S. L. (2022). Fighting cardiac fibrosis with CAR T cells. New England Journal of Medicine, 386(16), 1576-1578. PMID: 35443114 DOI:[https://doi.org/10.1056/NEJMcibr2201182 link]</ref> To overcome this, a technology has been created for the production of CAR-T cells directly in vivo. According to this technology, for the treatment of cardiac fibrosis after heart injury, mice were injected with lipid nanoparticles (LNPs) targeting to T cells through the expression of anti-CD5 (a T-cell marker) carrying a modified mRNA encoding a CAR against fibroblast activated protein. The in vivo generated CAR-T cells exerted anti-fibrotic properties and restored cardiac function in mice, holding promising therapeutic potential in a wide range of diseases progressing with fibrosis<ref>Rurik, J. G., Tombácz, I., Yadegari, A., Méndez Fernández, P. O., Shewale, S. V., Li, L., ... & Epstein, J. A. (2022). CAR T cells produced in vivo to treat cardiac injury. Science, 375(6576), 91-96. PMID: 34990237 DOI:[https://doi.org/10.1126/science.abm0594 link]</ref> The LNP-mRNA delivery system has advantages including having no integration in host genome, inexpensiveness, low toxicity and modifiability; on the other hand, it has certain disadvantages such as limited cell persistence caused by transient protein expression and limitations in preparation techniques.<ref>Yang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., ... & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. PMID: 36559175 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787894 link] DOI: 10.3390/pharmaceutics14122682</ref><ref>Ye, B., Hu, Y., Zhang, M., & Huang, H. (2022). Research advance in lipid nanoparticle-mRNA delivery system and its application in CAR-T cell therapy. Zhejiang da xue xue bao. Yi xue ban= Journal of Zhejiang University. Medical Sciences, 51(2), 185-191. PMID: 36161298 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353640 link] DOI: 10.3724/zdxbyxb-2022-0047</ref>





	Senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the '''senescence-associated protein urokinase plasminogen activator receptor (uPAR)''' can safely eliminate uPAR-positive senescent cells that accumulate during aging.<ref name="uPAR" /> Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.<ref>Amor, C., Fernández-Maestre, I., Chowdhury, S. et al. (2024). Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging https://doi.org/10.1038/s43587-023-00560-5		Senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the '''senescence-associated protein urokinase plasminogen activator receptor (uPAR)''' can safely eliminate uPAR-positive senescent cells that accumulate during aging.<ref name="uPAR" /> Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.<ref>Amor, C., Fernández-Maestre, I., Chowdhury, S. et al. (2024). Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nat Aging https://doi.org/10.1038/s43587-023-00560-5
	PMID: 37841853 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571605/ PMC10571605] DOI: 10.21203/rs.3.rs-3385749/v1</ref>		PMID: 37841853 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10571605/ PMC10571605] DOI: 10.21203/rs.3.rs-3385749/v1</ref>

			Alternatively, NK-cell-based therapies show promise in rejuvenating immunosenescence, eliminating senescent cells and alleviating SASPs, that lead to aging-associated diseases.<ref>Qi, C., & Liu, Q. (2023). Natural killer cells in aging and age-related diseases. Neurobiology of Disease, 183, 106156. PMID: 37209924 DOI: 10.1016/j.nbd.2023.106156</ref> The rapid development of inexpensive and accessible non-viral methods for engineering immune cells makes this approach a promising way to combat diseases of aging.<ref>Bexte, T., & Ullrich, E. (2024). Empowering virus-free CAR immune cell therapies. Molecular Therapy. 32(6), P1609-1611 PMID 38795701 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11184381 PMC 11184381] doi:10.1016/j.ymthe.2024.05.023</ref>

	==== Senolytic vaccination ====		==== Senolytic vaccination ====

Dmitry Dzhagarov: /* Senolytic CAR T cells */

2024-07-28T06:47:50Z

Senolytic CAR T cells

← Older revision		Revision as of 06:47, 28 July 2024
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	==== Senolytic CAR T cells ====		==== Senolytic CAR T cells ====
	Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/><ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>		Senescence in the immune compartment, as occurs with normal ageing, affects innate and adaptive immunity, in particular natural killer cell function, which cleanse the body of old inoperable cells, and potently drives senescence and age-related changes in solid organs.<ref name="immune"/><ref>Gabandé‐Rodríguez, E., Pfeiffer, M., & Mittelbrunn, M. (2023). Immuno (T) herapy for age‐related diseases. EMBO Molecular Medicine, 15(1), e16301. PMID: 36373340 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9832825 link] DOI: 10.15252/emmm.202216301</ref>
			Diminished Natural killer (NK) cells activity in elderly individuals is associated with disorders such as atherosclerosis, the development of hypertension<ref>Lee, Y. K., Suh, E., Oh, H., Haam, J. H., & Kim, Y. S. (2024). Decreased natural killer cell activity as a potential predictor of hypertensive incidence. Frontiers in Immunology, 15, 1376421. PMID: 38715619 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11074345/ PMC11074345] DOI: 10.3389/fimmu.2024.1376421</ref> and an elevated risk of mortality.<ref>Cho, A. R., Suh, E., Oh, H., Cho, B. H., Gil, M., & Lee, Y. K. (2023). Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study. International Journal of Molecular Sciences, 24(15), 12505. PMID: 37569879 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10419953/ PMC10419953] DOI: 10.3390/ijms241512505</ref><ref>Ogata, K., Yokose, N., Tamura, H., An, E., Nakamura, K., Dan, K., & Nomura, T. (1997). Natural killer cells in the late decades of human life. Clinical Immunology and Immunopathology, 84(3), 269-275. PMID: 9281385 DOI: 10.1006/clin.1997.4401</ref><ref>Ogata, K., An, E., Shioi, Y., Nakamura, K., Luo, S., Yokose, N., ... & Dan, K. (2001). Association between natural killer cell activity and infection in immunologically normal elderly people. Clinical & Experimental Immunology, 124(3), 392-397. PMID: 11472399 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906081/ PMC1906081] DOI: 10.1046/j.1365-2249.2001.01571.x</ref>

	Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref name="uPAR" >Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 PMC7426266] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.		Development of the CAR-T cells directed against a senescence-specific surface antigens has opened a new and very specific alternative to directly target pathological cells.<ref name="uPAR" >Huang, Y., & Liu, T. (2020). Step further towards targeted senolytic therapy: therapeutic potential of uPAR-CAR T cells for senescence-related diseases. Signal Transduction and Targeted Therapy, 5(1), 155. PMID: 32792494 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426266 PMC7426266] DOI: 10.1038/s41392-020-00268-7</ref><ref>Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., ... & Lowe, S. W. (2020). Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814), 127-132. PMID: 32555459 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583560 link] DOI: 10.1038/s41586-020-2403-9</ref> For example, in mice with cardiac fibrosis, adoptive transfer of T cells expressing a CAR against the fibroblast activation protein effectively reduced fibrosis and restored cardiac function after injury. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.<ref>Aghajanian, H., Kimura, T., Rurik, J. G., Hancock, A. S., Leibowitz, M. S., Li, L., ... & Epstein, J. A. (2019). Targeting cardiac fibrosis with engineered T cells. Nature, 573(7774), 430-433. PMID: 31511695 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752964 link] DOI: 10.1038/s41586-019-1546-z</ref><ref>Ferrer-Curriu, G., Soler-Botija, C., Charvatova, S., Motais, B., Roura, S., Galvez-Monton, C., ... & Genís, A. B. (2023). Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy. Biomedicine & Pharmacotherapy, 158, 114061.
	PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or p16<sup>INK4a</sup> overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>		PMID: 36495661 DOI:[https://doi.org/10.1016/j.biopha.2022.114061 link]</ref> Because natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells, NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence. Сhimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or p16<sup>INK4a</sup> overexpression ''in vitro''. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects.<ref>Yang, D., Sun, B., Li, S., Wei, W., Liu, X., Cui, X., ... & Zhao, X. (2023). NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Science Translational Medicine, 15(709), eadd1951. PMID: 37585504 DOI: 10.1126/scitranslmed.add1951</ref>

Dmitry Dzhagarov: /* Senescent cells as a factor of aging and age-associated diseases */

2024-06-28T08:10:22Z

Senescent cells as a factor of aging and age-associated diseases

← Older revision		Revision as of 08:10, 28 June 2024
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	e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.		e13826 https://doi.org/10.1111/acel.13826</ref> Senescent cells can play a role in the body's response to stress, including tissue damage and oxidative stress. When cells experience stress or DNA damage, they may enter a state of senescence to prevent further division and growth, which can help to limit the spread of damaged or potentially cancerous cells. In this way, senescence can act as a barrier to the development of cancer.

	Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.		Although senescent cells can play a role in the body's response to stress and tissue repair, their accumulation over time is thought to contribute to the aging process and the development of age-related diseases.<ref>Lemaitre, J. M. (2024). Looking for the philosopher's stone: Emerging approaches to target the hallmarks of aging in the skin. Journal of the European Academy of Dermatology and Venereology, 38, 5-14.https://doi.org/10.1111/jdv.19820</ref>
	Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP\|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>		Among its detrimental actions, senescent cells, even though their abundance in aging or diseased tissues is very low,<ref name="Achilles">Zhu, Y. I., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., ... & Kirkland, J. L. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658. PMID: 25754370 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078 link] DOI: 10.1111/acel.12344</ref> '''contribute to chronic inflammation and tissue degeneration mainly derived from the production of the pro-inflammatory cytokines, growth factors, and extracellular matrix proteases that comprise their secretion - [[Cellular_senescence#SASP\|'''SASP''']] (senescence associated secretory phenotype)''', which can contribute to tissue damage, inflammation, and the progression of age-related diseases.<ref name="target">Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022). Cellular senescence: a key therapeutic target in aging and diseases. Journal of Clinical Investigation, 132(15), e158450. PMID: 35912854 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9337830 link] DOI: 10.1172/JCI158450</ref> In this regard, the SASP was shown to alter tissue function and to accelerate the aging process by recruiting immune cells and extracellular matrix-remodeling complexes. Accordingly, '''in young individuals, senescence plays a key role in tumor surveillance and tissue repair, whereas in older individuals, the accumulation of senescent cells has been associated with tissue dysfunction and chronic conditions like cancer, cardiovascular disease and neurodegeneration'''.<ref name="target"/> Importantly, clearance of senescent cells using genetic approaches or senolytic drugs has been shown to improve tissue function in different in vivo models of aging and age-associated diseases.<ref name="target"/> In addition, '''senescent cells can also promote the development of cancer by evading cell death and contributing to the accumulation of genetic mutations'''.<ref>Liu, H., Zhao, H., & Sun, Y. (2022). Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies. In Seminars in Cancer Biology (Vol. 86, pp. 769-781). Academic Press. PMID: 34799201 DOI:[https://doi.org/10.1016/j.semcancer.2021.11.004 link] </ref> They can also impair the function of nearby healthy cells, leading to a decline in tissue and organ function - a phenomenon known as '''paracrine senescence''', where secreted senescence factors and extracellular vesicles (EVs)<ref>Kim, H. J., Kim, G., Lee, J., Lee, Y., & Kim, J. H. (2022). Secretome of stem cells: roles of extracellular vesicles in diseases, stemness, differentiation, and reprogramming. Tissue Engineering and Regenerative Medicine, 1-15. PMID: 34817808 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782975 link] DOI: 10.1007/s13770-021-00406-4</ref> can induce senescence (secondary due to '''paracrine senescence niche''') of neighboring cells.<ref>Urman, M. A., John, N. S., & Lee, C. (2023). Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration. bioRxiv, 2023-01. Doi: [https://doi.org/10.1101/2023.01.15.524122 10.1101/2023.01.15.524122]</ref><ref>Lucas, V., Cavadas, C., & Aveleira, C. A. (2023). Cellular senescence: from mechanisms to current biomarkers and senotherapies. Pharmacological Reviews. PMID: 36732079 DOI:[https://doi.org/10.1124/pharmrev.122.000622 link]</ref>

Dmitry Dzhagarov: /* Senescent cells as a factor of aging and age-associated diseases */

2024-06-21T19:41:39Z

Senescent cells as a factor of aging and age-associated diseases

← Older revision		Revision as of 19:41, 21 June 2024
Line 16:		Line 16:
	Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" /><ref name=":1">Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., ... & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. ''Science'', ''378''(6616), 192-201.</ref>.		Three characteristics thought to define senescent cells are irreversible cell cycle arrest, the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP), and resistance to apoptosis. However, it has become increasingly appreciated that there senescent cells are difficult to define, as benefits or detriments to health depend on the context, e.g. being tissue or organ-specific<ref name=":0" /><ref name=":1">Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., ... & Peng, T. (2022). Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung. ''Science'', ''378''(6616), 192-201.</ref>.
	[[File:Senescent.jpg\|thumb\| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]		[[File:Senescent.jpg\|thumb\| The central role of senescent cells in the occurrence of diseases of the elderly.<ref name="target"/>]]
	Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref name=":1" /><ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>		Senescence is often viewed as a double-edged sword with both beneficial and detrimental effects.<ref>João Pedro de Magalhães (2024). [https://www.science.org/doi/10.1126/science.adj7050 Cellular senescence in normal physiology].Science, 384, 1300-1301. DOI:10.1126/science.adj7050</ref><ref name=":1" /><ref>Idda, M. L., McClusky, W. G., Lodde, V., Munk, R., Abdelmohsen, K., Rossi, M., & Gorospe, M. (2020). Survey of senescent cell markers with age in human tissues. Aging (Albany NY), 12(5), 4052. PMID: 32160592 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093180 link] DOI: 10.18632/aging.102903</ref>

	Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),		Among its beneficial actions, '''senescence was shown to promote wound repair, developmental morphogenesis, and tumor suppression''', mainly by triggering cell cycle arrest and the release of specific cytokines necessary for wound healing.<ref>Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., ... & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733. PMID: 25499914 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349629 link] DOI: 10.1016/j.devcel.2014.11.012</ref><ref>Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., ... & Keyes, W. M. (2017). The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes & development, 31(2), 172-183. PMID: 28143833 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322731 link] DOI: 10.1101/gad.290635.116</ref> Senescent cells can contribute to tissue repair by secreting growth factors that promote the proliferation and differentiation of nearby stem cells. This process is important for the healing of injuries and the maintenance of tissue and organ function. A study of salamander limb regeneration found that implanted senescent cells, prior to promote cell proliferation, enhance muscle dedifferentiation, a critical process underlying successful limb regeneration, and that senescent cells are able to modulate this muscle dedifferentiation directly, through the secretion of paracrine factors including WNT and FGF ligands.<ref>Walters, H., Troyanovskiy, K., & Yun, M. H. (2023). Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation. Aging Cell, 22(6),

Dmitry Dzhagarov: /* Small molecules of senolytics */

2024-04-07T07:29:28Z

Small molecules of senolytics

← Older revision		Revision as of 07:29, 7 April 2024
Line 33:		Line 33:

	== Small molecules of senolytics ==		== Small molecules of senolytics ==
			Therapeutics for killing senescent cells could take the form of senolytic small molecules or immune-based clearance (antibodies or cytotoxic T cells).<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref> Senescent cells rely on prosurvival stress response adaptations to avoid apoptosis. This suggests that an attractive senescent cell killing approach would be to use small-molecule inhibitors to block cell death-resistance pathways, thereby using the endogenous stress to drive these cells into apoptosis. Existing inhibitors of prosurvival pathways used in cancer therapy may have utility for senescent cell killing, and could be even more effective for this use given that senescent cells, unlike cancer, do not proliferate.
	[[File:Classification of senolytics.jpg\|thumb\|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]		[[File:Classification of senolytics.jpg\|thumb\|Classification of senolytics according to Power H. et al., 2023.<ref>Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023). Strategies for senolytic drug discovery. Aging Cell, e13948. PMID: 37548098 [https://doi.org/10.1111/acel.13948 DOI: 10.1111/acel.13948]</ref>]]
	<ref>Massoud, G. P., Eid, A. E., Booz, G. W., Rached, L., Yabluchanskiy, A., & Zouein, F. A. (2023). Senolytics in diseases: killing to survive. In Anti-Aging Pharmacology (pp. 245-267). Academic Press. https://doi.org/10.1016/B978-0-12-823679-6.00009-6</ref>

	=== [[Dasatinib]] + [[Quercetin]] ===		=== [[Dasatinib]] + [[Quercetin]] ===
	[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.		[[Dasatinib]] and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.

Dmitry Dzhagarov: /* Salvestrols */

2024-01-28T15:20:16Z

Salvestrols

← Older revision		Revision as of 15:20, 28 January 2024
Line 97:		Line 97:

	=== Salvestrols ===		=== Salvestrols ===
	Salvestrol (lat. salvus - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens. Under the influence of the cytochrome P450 enzyme CYP1B1, which is ~~produced~~ in large quantities in cancer cells<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of target cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>		Salvestrol (lat. ''salvus'' - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens.
			Under the influence of the '''cytochrome P450 enzyme CYP1B1''', which was reported to be involved in performance of two important factors of aging: mitochondrial function and reactive oxygen species (ROS) production,<ref>Lu, Y., Nanayakkara, G., Sun, Y., Liu, L., Xu, K., Drummer IV, C., ... & Yang, X. (2021). Procaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation. Redox Biology, 47, 102142. PMID: 34598017 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487079/ PMC8487079] DOI: 10.1016/j.redox.2021.102142 </ref> and which is expressed in large quantities in cancer cells<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence,<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of target cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>

	Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena, rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>		Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena, rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>

Dmitry Dzhagarov: /* Salvestrols */

2024-01-28T09:03:06Z

Salvestrols

← Older revision		Revision as of 09:03, 28 January 2024
Line 99:		Line 99:
	Salvestrol (lat. salvus - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens. Under the influence of the cytochrome P450 enzyme CYP1B1, which is produced in large quantities in cancer cells<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of target cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>		Salvestrol (lat. salvus - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens. Under the influence of the cytochrome P450 enzyme CYP1B1, which is produced in large quantities in cancer cells<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of target cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>

	Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena ~~and~~ rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>		Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena, rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>

	=== p53-regulated apoptosis inducers ===		=== p53-regulated apoptosis inducers ===

Dmitry Dzhagarov: /* Salvestrols */

2024-01-28T09:01:04Z

Salvestrols

← Older revision		Revision as of 09:01, 28 January 2024
Line 97:		Line 97:

	=== Salvestrols ===		=== Salvestrols ===
	Salvestrol (lat. salvus - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens. Under the influence of the cytochrome P450 enzyme CYP1B1, which is produced in large quantities ~~only~~ in cancer cells,<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of ~~cancer~~ cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>		Salvestrol (lat. salvus - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens. Under the influence of the cytochrome P450 enzyme CYP1B1, which is produced in large quantities in cancer cells<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of target cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>

	Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena and rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>		Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena and rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>

Dmitry Dzhagarov: /* Fibrates */

2024-01-28T08:58:44Z

Fibrates

← Older revision		Revision as of 08:58, 28 January 2024
Line 95:		Line 95:
	=== Fibrates ===		=== Fibrates ===
	Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>		Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and osteoarthritis chondrocytes.<ref>Nogueira-Recalde, U., Lorenzo-Gómez, I., Blanco, F. J., Loza, M. I., Grassi, D., Shirinsky, V., ... & Caramés, B. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine, 45, 588-605. PMID: 31285188 PMC [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642320 link] DOI: 10.1016/j.ebiom.2019.06.049</ref>

			=== Salvestrols ===
			Salvestrol (lat. salvus - healthy, unharmed) is a very special group of secondary plant substances that are part of the plant’s natural defense system. They are especially formed when the plant is attacked by pathogens. Under the influence of the cytochrome P450 enzyme CYP1B1, which is produced in large quantities only in cancer cells,<ref>Murray, G. I., Taylor, M. C., McFadyen, M. C., McKay, J. A., Greenlee, W. F., Burke, M. D., & Melvin, W. T. (1997). Tumor-specific expression of cytochrome P450 CYP1B1. Cancer research, 57(14), 3026-3031. PMID: 9230218</ref><ref>Yuan, B., Liu, G., Dai, Z., Wang, L., Lin, B., & Zhang, J. (2022). CYP1B1: A Novel Molecular Biomarker Predicts Molecular Subtype, Tumor Microenvironment, and Immune Response in 33 Cancers. Cancers, 14(22), 5641. PMID: 36428734 PMCID: PMC9688555 DOI: 10.3390/cancers14225641</ref> and due to cellular senescence<ref>Ye, G., Li, J., Yu, W., Xie, Z., Zheng, G., Liu, W., ... & Shen, H. (2023). ALKBH5 facilitates CYP1B1 mRNA degradation via m6A demethylation to alleviate MSC senescence and osteoarthritis progression. Experimental & Molecular Medicine, 55(8), 1743-1756. PMID: 37524872 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474288/ PMC10474288] DOI: 10.1038/s12276-023-01059-0</ref> salvestrols can be converted into metabolites that cause the death of cancer cells.<ref>Tan, H. L., Butler, P. C., Burke, M. D., & Potter, G. A. (2007). Salvestrols: a new perspective in nutritional research. Journal of Orthomolecular Medicine, 22(1), 39-47.</ref><ref>DIET, R., & SHOP, N. S. (2012). Salvestrols cause cancer cell death. ICON, 2011(2010), 2010. https://www.canceractive.com/article/Salvestrols,-Protection-and-Correction</ref><ref>Tan, H. L., Beresford, K., Butler, P. C., Potter, G. A., & Burke, M. D. (2007). Salvestrols-natural anticancer prodrugs in the diet. In Journal of Pharmacy and Pharmacology (Vol. 59, pp. A59-A59).</ref>

			Plants with a generally higher salvestrol content from organic farming include artichokes, asparagus, watercress, rocket, spinach, pumpkin, olives, currants, apples, rose hip, strawberries, sage, mint, dandelion, plantain, milk thistle, agrimony, lemon verbena and rooibos tea.<ref>Georg, C. S., Center, L. S., Protocol, L. T., & PDT, P. T. T. Salvestrols in Cancer and Chronic Diseases 15. December 2019 16. March 2021 Dr. Douwes informs/Prevention.</ref> and especially tangerines.<ref>Ferenčić, D., Gluhić, D., & Dudaš, S. (2016). Hranjiva vrijednost mandarina (Citrus reticulata Blanco, Citrus nobilis Lour). Glasnik zaštite bilja, 39(3), 46-52. https://hrcak.srce.hr/162239</ref>

	=== p53-regulated apoptosis inducers ===		=== p53-regulated apoptosis inducers ===