CD38 - Revision history

Dmitry Dzhagarov: /* CD38 inhibitors */

2023-09-20T20:55:23Z

CD38 inhibitors

Dmitry Dzhagarov: /* CD38 inhibitors */

2023-06-01T11:31:05Z

CD38 inhibitors

← Older revision		Revision as of 11:31, 1 June 2023
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	'''78c has been shown to increase lifespan (average by 17% and maximal by 14%)''' and protect against aging-induced health loss in aged male mice.<ref>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref>		'''78c has been shown to increase lifespan (average by 17% and maximal by 14%)''' and protect against aging-induced health loss in aged male mice.<ref>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref>

	Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref>		Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref> Administration of the CD38 inhibitor MK-0159 reverses mitochondrial defects and restores CD8+ T cells function against infections in mice and so substantially improves the pathology linked to viral infection.<ref>Chen, P. M., Katsuyama, E., Satyam, A., Li, H., Rubio, J., Jung, S., ... & Tsokos, G. C. (2022). CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy. Science Advances, 8(24), eabo4271. PMID: 35704572 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9200274 9200274] DOI: 10.1126/sciadv.abo4271</ref>

	The potential to treat various diseases associated with [[NAD+\|NAD<sup>+</sup>]] deficiency without the potential side effects of small molecules and cytotoxic antibodies has an IgG (immunoglobulin) antibody '''TNB-738''' that neither crosses the cell membrane nor the blood–brain barrier. The desired mechanism of action of TNB-738 is strictly enzyme inhibition without CD38<sup>+</sup> cell depletion, thus avoiding side-effects associated with the lysis of subpopulations of immune cells, such as monocytes, effector T cells, and NK cells.<ref>Ugamraj, H. S., Dang, K., Ouisse, L. H., Buelow, B., Chini, E. N., Castello, G., ... & Dalvi, P. (2022). TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs, 14(1), 2095949 PMID:35867844 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311320 9311320] DOI:[https://doi.org/10.1080/19420862.2022.2095949 10.1080/19420862.2022.2095949] </ref>		The potential to treat various diseases associated with [[NAD+\|NAD<sup>+</sup>]] deficiency without the potential side effects of small molecules and cytotoxic antibodies has an IgG (immunoglobulin) antibody '''TNB-738''' that neither crosses the cell membrane nor the blood–brain barrier. The desired mechanism of action of TNB-738 is strictly enzyme inhibition without CD38<sup>+</sup> cell depletion, thus avoiding side-effects associated with the lysis of subpopulations of immune cells, such as monocytes, effector T cells, and NK cells.<ref>Ugamraj, H. S., Dang, K., Ouisse, L. H., Buelow, B., Chini, E. N., Castello, G., ... & Dalvi, P. (2022). TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs, 14(1), 2095949 PMID:35867844 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311320 9311320] DOI:[https://doi.org/10.1080/19420862.2022.2095949 10.1080/19420862.2022.2095949] </ref>

Dmitry Dzhagarov: /* CD38 as a metabolic sensor and regulator */

2023-05-13T15:53:35Z

CD38 as a metabolic sensor and regulator

← Older revision		Revision as of 15:53, 13 May 2023
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	[[NAD+\|NAD<sup>+</sup>]] levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. <ref name=”Chini” /><ref name=”dictates” /> <ref name=”Sinclair” /> It was shown that the enzyme CD38 is one of the main NAD-degrading enzymes in mammalian tissues.<ref name=”dictates” /><ref name=”Hogan” /> In addition to NAD<sup>+</sup>, CD38 metabolizes extracellular NAD<sup>+</sup> precursors Nicotinamide mononucleotide (NMN) and Nicotinamide riboside (NR) prior to their transport into the cell for NAD<sup>+</sup> biosynthesis.<ref name=”dictates” />		[[NAD+\|NAD<sup>+</sup>]] levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. <ref name=”Chini” /><ref name=”dictates” /> <ref name=”Sinclair” /> It was shown that the enzyme CD38 is one of the main NAD-degrading enzymes in mammalian tissues.<ref name=”dictates” /><ref name=”Hogan” /> In addition to NAD<sup>+</sup>, CD38 metabolizes extracellular NAD<sup>+</sup> precursors Nicotinamide mononucleotide (NMN) and Nicotinamide riboside (NR) prior to their transport into the cell for NAD<sup>+</sup> biosynthesis.<ref name=”dictates” />

	It was discovered that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce pro-inflammatory M1-like macrophages to proliferate and express CD38. <ref>Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., ... & Verdin, E. (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. ''Nature metabolism'', ''2''(11), 1265-1283. PMID: 33199924 PMC7908681 DOI:[https://doi.org/10.1038/s42255-020-00305-3 10.1038/s42255-020-00305-3]</ref> <ref> Chini, C., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., ... & Chini, E. N. (2020). CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. ''Nature metabolism'', ''2''(11), 1284-1304. PMID: 33199925 PMC8752031 DOI:[https://doi.org/10.1038/s42255-020-00298-z 10.1038/s42255-020-00298-z]</ref> This highlights senescent cells as an important factor in NAD<sup>+</sup> decline because the accumulation of senescent cells with age leads to increased systemic secretion of the pro-inflammatory SASP, which in turn leads to elevation of cellular CD38 expression and a concurrent decrease in NAD<sup>+</sup> levels. '''[[NAD+\|NAD<sup>+</sup>]] restoration has been identified as a key therapeutic target that can positively impact many of the hallmarks of cellular aging'''.<ref>Conlon, N. J. (2022). The Role of NAD+ in Regenerative Medicine. Plastic and reconstructive surgery, 150, 41S-48S. PMID:36170435 PMC9512238 DOI:[https://doi.org/10.1097/PRS.0000000000009673 10.1097/PRS.0000000000009673]</ref>		It was discovered that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, [[Cellular_senescence#SASP\|'''SASP''']]) induce pro-inflammatory M1-like macrophages to proliferate and express CD38. <ref>Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., ... & Verdin, E. (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. ''Nature metabolism'', ''2''(11), 1265-1283. PMID: 33199924 PMC7908681 DOI:[https://doi.org/10.1038/s42255-020-00305-3 10.1038/s42255-020-00305-3]</ref> <ref> Chini, C., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., ... & Chini, E. N. (2020). CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. ''Nature metabolism'', ''2''(11), 1284-1304. PMID: 33199925 PMC8752031 DOI:[https://doi.org/10.1038/s42255-020-00298-z 10.1038/s42255-020-00298-z]</ref> This highlights senescent cells as an important factor in NAD<sup>+</sup> decline because the accumulation of senescent cells with age leads to increased systemic secretion of the pro-inflammatory SASP, which in turn leads to elevation of cellular CD38 expression and a concurrent decrease in NAD<sup>+</sup> levels. '''[[NAD+\|NAD<sup>+</sup>]] restoration has been identified as a key therapeutic target that can positively impact many of the hallmarks of cellular aging'''.<ref>Conlon, N. J. (2022). The Role of NAD+ in Regenerative Medicine. Plastic and reconstructive surgery, 150, 41S-48S. PMID:36170435 PMC9512238 DOI:[https://doi.org/10.1097/PRS.0000000000009673 10.1097/PRS.0000000000009673]</ref>
	Boosting NAD<sup>+</sup> via genetic or pharmacological CD38 targeting or NAD<sup>+</sup> precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. <ref name=”fibrosis”>Shi, B., Wang, W., Korman, B., Kai, L., Wang, Q., Wei, J., ... & Varga, J. (2021). Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis. Iscience, 24(1), 101902. PMID: 33385109 PMC7770554 DOI:[https://doi.org/10.1016/j.isci.2020.101902 10.1016/j.isci.2020.101902]</ref> Long-living-individuals (>95 years), carriers (both hetero and homozygous) of longevity-associated variant LAV-BPIFB4 gene displayed significantly higher NAD<sup>+</sup> circulating level, when compared with no-carriers, apparently due to reduction of the frequency of CD38<sup>+</sup> immune cells<ref> Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., ... & Puca, A. A. (2022). "Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline". Cell death & disease, 13(1), 1-10. PMID: 35087020 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792139 8792139] DOI:[https://doi.org/10.1038/s41419-022-04535-z 10.1038/s41419-022-04535-z]</ref> NAD<sup>+</sup> repletion with the NAD<sup>+</sup> precursor nicotinamide riboside (NR) improved mitochondrial and stem cell function and enhanced life span in mice.<ref>Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., ... & Auwerx, J. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443. PMID: 27127236 DOI:[https://doi.org/10.1126/science.aaf2693 10.1126/science.aaf2693]</ref> However, increasing NAD<sup>+</sup> using a precursor without first inhibiting CD38 may ‘fuel’ CD38-mediated inflammation due to increased secretion of pro-inflammatory tumorigenic SASP cytokines leading to elevation of cellular CD38 expression and so to repeat decrease in NAD<sup>+</sup> levels.<ref>Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., ... & Zhang, R. (2019). NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nature cell biology, 21(3), 397-407. PMID: 30778219 PMC6448588 DOI:[https://doi.org/10.1038/s41556-019-0287-4 10.1038/s41556-019-0287-4]</ref>		Boosting NAD<sup>+</sup> via genetic or pharmacological CD38 targeting or NAD<sup>+</sup> precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. <ref name=”fibrosis”>Shi, B., Wang, W., Korman, B., Kai, L., Wang, Q., Wei, J., ... & Varga, J. (2021). Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis. Iscience, 24(1), 101902. PMID: 33385109 PMC7770554 DOI:[https://doi.org/10.1016/j.isci.2020.101902 10.1016/j.isci.2020.101902]</ref> Long-living-individuals (>95 years), carriers (both hetero and homozygous) of longevity-associated variant LAV-BPIFB4 gene displayed significantly higher NAD<sup>+</sup> circulating level, when compared with no-carriers, apparently due to reduction of the frequency of CD38<sup>+</sup> immune cells<ref> Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., ... & Puca, A. A. (2022). "Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline". Cell death & disease, 13(1), 1-10. PMID: 35087020 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792139 8792139] DOI:[https://doi.org/10.1038/s41419-022-04535-z 10.1038/s41419-022-04535-z]</ref> NAD<sup>+</sup> repletion with the NAD<sup>+</sup> precursor nicotinamide riboside (NR) improved mitochondrial and stem cell function and enhanced life span in mice.<ref>Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., ... & Auwerx, J. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443. PMID: 27127236 DOI:[https://doi.org/10.1126/science.aaf2693 10.1126/science.aaf2693]</ref> However, increasing NAD<sup>+</sup> using a precursor without first inhibiting CD38 may ‘fuel’ CD38-mediated inflammation due to increased secretion of pro-inflammatory tumorigenic SASP cytokines leading to elevation of cellular CD38 expression and so to repeat decrease in NAD<sup>+</sup> levels.<ref>Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., ... & Zhang, R. (2019). NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nature cell biology, 21(3), 397-407. PMID: 30778219 PMC6448588 DOI:[https://doi.org/10.1038/s41556-019-0287-4 10.1038/s41556-019-0287-4]</ref>
	Thus, dietary NAD<sup>+</sup> augmenting supplement should be administered with precision to balance the advantageous anti-ageing effects with potential detrimental pro-tumorigenic side effects.<ref>Maric, T., Bazhin, A., Khodakivskyi, P., Mikhaylov, G., Solodnikova, E., Yevtodiyenko, A., ... & Goun, E. (2023). A bioluminescent-based probe for in vivo non-invasive monitoring of nicotinamide riboside uptake reveals a link between metastasis and NAD+ metabolism. Biosensors and Bioelectronics, 220, 114826. PMID: 36371959 DOI:[https://doi.org/10.1016/j.bios.2022.114826 10.1016/j.bios.2022.114826]</ref>		Thus, dietary NAD<sup>+</sup> augmenting supplement should be administered with precision to balance the advantageous anti-ageing effects with potential detrimental pro-tumorigenic side effects.<ref>Maric, T., Bazhin, A., Khodakivskyi, P., Mikhaylov, G., Solodnikova, E., Yevtodiyenko, A., ... & Goun, E. (2023). A bioluminescent-based probe for in vivo non-invasive monitoring of nicotinamide riboside uptake reveals a link between metastasis and NAD+ metabolism. Biosensors and Bioelectronics, 220, 114826. PMID: 36371959 DOI:[https://doi.org/10.1016/j.bios.2022.114826 10.1016/j.bios.2022.114826]</ref>

Dmitry Dzhagarov: /* CD38 inhibitors */

2023-04-27T16:40:56Z

CD38 inhibitors

← Older revision		Revision as of 16:40, 27 April 2023
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	Anthocyanins, such as luteolinidin, protects endothelial and myocardial function in the postischemic heart through CD38 inhibition.<ref> Boslett, J., Hemann, C., Zhao, Y. J., Lee, H. C., & Zweier, J. L. (2017). Luteolinidin protects the postischemic heart through CD38 inhibition with preservation of NAD (P)(H). Journal of Pharmacology and Experimental Therapeutics, 361(1), 99-108. PMID: 28108596 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363772 5363772] DOI: 10.1124/jpet.116.239459</ref>		Anthocyanins, such as luteolinidin, protects endothelial and myocardial function in the postischemic heart through CD38 inhibition.<ref> Boslett, J., Hemann, C., Zhao, Y. J., Lee, H. C., & Zweier, J. L. (2017). Luteolinidin protects the postischemic heart through CD38 inhibition with preservation of NAD (P)(H). Journal of Pharmacology and Experimental Therapeutics, 361(1), 99-108. PMID: 28108596 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363772 5363772] DOI: 10.1124/jpet.116.239459</ref>
			[[File:CD38 inhibitor 78c.jpg\|thumb\|Potent CD38 inhibitor '''78c''', can act ''in vivo''.]]
	In diseases associated with aging, for therapy that increases NAD<sup>+</sup> can be used a '''78c''' inhibitor.<ref>Chini, E. N., Chini, C. C., Netto, J. M. E., de Oliveira, G. C., & van Schooten, W. (2018). The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in pharmacological sciences, 39(4), 424-436. PMID:29482842 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288 5885288] doi:10.1016/j.tips.2018.02.001</ref><ref name=”Tarragó”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140 5935140] doi:10.1016/j.cmet.2018.03.016</ref> For example, 78c increased the level of NAD in the liver by 536% just two hours after ingestion.<ref>Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. C. (2015). Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors. Journal of medicinal chemistry, 58(8), 3548-3571. PMID 25828863 doi:10.1021/jm502009h</ref> Treatment of old mice with the NADase 78c inhibitor markedly reduced the accumulation of inflammatory cells in tissues and significantly reduced the appearance of fibrotic and inflammatory changes with aging in muscles <ref name=”Tarragó” /> , as well as in the skin, lungs and peritoneal mucosa.<ref name=”fibrosis” /> In in vitro experiments on mouse hearts, treatment with 78c significantly reduced the effects of myocardial infarction.<ref>Boslett, J., Reddy, N., Alzarie, Y. A., & Zweier, J. L. (2019). Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury. Journal of Pharmacology and Experimental Therapeutics, 369(1), 55-64. PMID 30635470 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413770 6413770] doi:10.1124/jpet.118.254557</ref>[[File:TNB-738-mediated CD38 inhibition.jpg\|thumb\|Intracellular NAD+ boosting by TNB-738-mediated CD38 inhibition (Ugamraj et al., 2022)]]		In diseases associated with aging, for therapy that increases NAD<sup>+</sup> can be used a '''78c''' inhibitor.<ref>Chini, E. N., Chini, C. C., Netto, J. M. E., de Oliveira, G. C., & van Schooten, W. (2018). The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in pharmacological sciences, 39(4), 424-436. PMID:29482842 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288 5885288] doi:10.1016/j.tips.2018.02.001</ref><ref name=”Tarragó”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140 5935140] doi:10.1016/j.cmet.2018.03.016</ref> For example, 78c increased the level of NAD in the liver by 536% just two hours after ingestion.<ref>Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. C. (2015). Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors. Journal of medicinal chemistry, 58(8), 3548-3571. PMID 25828863 doi:10.1021/jm502009h</ref> Treatment of old mice with the NADase 78c inhibitor markedly reduced the accumulation of inflammatory cells in tissues and significantly reduced the appearance of fibrotic and inflammatory changes with aging in muscles <ref name=”Tarragó” /> , as well as in the skin, lungs and peritoneal mucosa.<ref name=”fibrosis” /> In in vitro experiments on mouse hearts, treatment with 78c significantly reduced the effects of myocardial infarction.<ref>Boslett, J., Reddy, N., Alzarie, Y. A., & Zweier, J. L. (2019). Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury. Journal of Pharmacology and Experimental Therapeutics, 369(1), 55-64. PMID 30635470 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413770 6413770] doi:10.1124/jpet.118.254557</ref>[[File:TNB-738-mediated CD38 inhibition.jpg\|thumb\|Intracellular NAD+ boosting by TNB-738-mediated CD38 inhibition (Ugamraj et al., 2022)]]

Andrea: hyperlinks and category changes

2022-12-27T11:43:49Z

hyperlinks and category changes

← Older revision		Revision as of 11:43, 27 December 2022
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	== CD38 plays crucial roles in calcium signaling ==		== CD38 plays crucial roles in calcium signaling ==

	CD38 is a single-pass transmembrane enzyme catalyzing basically the synthesis of two nucleotide second messengers, cyclic ADP-ribose (cADPR) from [[NAD+\| NAD<sup>+</sup>]] ~~and~~ nicotinic acid adenine dinucleotide phosphate (NAADP) from NADP. <ref name=”topology”>Lee, H. C., Deng, Q. W., & Zhao, Y. J. (2022). The calcium signaling enzyme CD38-a paradigm for membrane topology defining distinct protein functions. Cell Calcium, 101, 102514. PMID:34896700 [https://doi.org/10.1016/j.ceca.2021.102514 DOI:10.1016/j.ceca.2021.102514] </ref>		CD38 is a single-pass transmembrane enzyme catalyzing basically the synthesis of two nucleotide second messengers, cyclic ADP-ribose (cADPR) from [[NAD+\| NAD<sup>+</sup>]] and nicotinic acid adenine dinucleotide phosphate (NAADP) from NADP. <ref name=”topology”>Lee, H. C., Deng, Q. W., & Zhao, Y. J. (2022). The calcium signaling enzyme CD38-a paradigm for membrane topology defining distinct protein functions. Cell Calcium, 101, 102514. PMID:34896700 [https://doi.org/10.1016/j.ceca.2021.102514 DOI:10.1016/j.ceca.2021.102514] </ref>

	CD38 exists in two opposite membrane orientations. If its catalytic domain facing the cytosol, it is responsible for producing cellular cADPR that mediates the mobilization of the endoplasmic Ca<sup>2+</sup> -stores in response to a wide range of stimuli<ref name=”topology” />. In an opposite orientation, it is a surface receptor mediating extracellular functions such as immune cell adhesion, activation and proliferation, as well as the release of pro-inflammatory and regulatory cytokines. <ref name=”Paracrine”>Astigiano, C., Benzi, A., Laugieri, M. E., Piacente, F., Sturla, L., Guida, L., ... & De Flora, A. (2022). Paracrine ADP Ribosyl Cyclase-Mediated Regulation of Biological Processes. Cells, 11(17), 2637. [https://pubmed.ncbi.nlm.nih.gov/36078044 PMID:36078044] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454491/ PMC9454491] [https://doi.org/10.3390/cells11172637 DOI: 10.3390/cells11172637] </ref> At an acidic pH, surface CD38 produces yet another Ca<sup>2+</sup>-messenger, NAADP, when delivered to the endo-lysosomes by induced endocytosis. <ref name=”topology” /> <ref>Wo, Y. J., Gan, A. S. P., Lim, X., Tay, I. S. Y., Lim, S., Lim, J. C. T., & Yeong, J. P. S. (2019). The roles of CD38 and CD157 in the solid tumor microenvironment and cancer immunotherapy. Cells, 9(1), 26. [https://pubmed.ncbi.nlm.nih.gov/31861847/ PMID: 31861847] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017359 PMC7017359] [https://doi.org/10.3390/cells9010026 DOI: 10.3390/cells9010026]</ref>		CD38 exists in two opposite membrane orientations. If its catalytic domain facing the cytosol, it is responsible for producing cellular cADPR that mediates the mobilization of the endoplasmic Ca<sup>2+</sup> -stores in response to a wide range of stimuli<ref name=”topology” />. In an opposite orientation, it is a surface receptor mediating extracellular functions such as immune cell adhesion, activation and proliferation, as well as the release of pro-inflammatory and regulatory cytokines. <ref name=”Paracrine”>Astigiano, C., Benzi, A., Laugieri, M. E., Piacente, F., Sturla, L., Guida, L., ... & De Flora, A. (2022). Paracrine ADP Ribosyl Cyclase-Mediated Regulation of Biological Processes. Cells, 11(17), 2637. [https://pubmed.ncbi.nlm.nih.gov/36078044 PMID:36078044] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454491/ PMC9454491] [https://doi.org/10.3390/cells11172637 DOI: 10.3390/cells11172637] </ref> At an acidic pH, surface CD38 produces yet another Ca<sup>2+</sup>-messenger, NAADP, when delivered to the endo-lysosomes by induced endocytosis. <ref name=”topology” /> <ref>Wo, Y. J., Gan, A. S. P., Lim, X., Tay, I. S. Y., Lim, S., Lim, J. C. T., & Yeong, J. P. S. (2019). The roles of CD38 and CD157 in the solid tumor microenvironment and cancer immunotherapy. Cells, 9(1), 26. [https://pubmed.ncbi.nlm.nih.gov/31861847/ PMID: 31861847] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017359 PMC7017359] [https://doi.org/10.3390/cells9010026 DOI: 10.3390/cells9010026]</ref>
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	== CD38 as a metabolic sensor and regulator ==		== CD38 as a metabolic sensor and regulator ==

	An important role in various cellular processes, including metabolism, cellular signaling, epigenetics and DNA repair plays NAD<sup>+</sup> (Nicotinamide adenine dinucleotide) a critical redox coenzyme. <ref name=”Chini”>Chini, C. C., Tarragó, M. G., & Chini, E. N. (2017). NAD and the aging process: Role in life, death and everything in between. Molecular and cellular endocrinology, 455, 62-74. [https://pubmed.ncbi.nlm.nih.gov/27825999/ PMID: 27825999] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419884/ PMC5419884] [https://doi.org/10.1016/j.mce.2016.11.003 doi:[https://doi.org/10.1016/j.mce.2016.11.003]</ref> <ref name=”dictates”>Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., ... & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139. PMID: 27304511 PMC4911708 DOI:[https://doi.org/10.1016/j.cmet.2016.05.006 10.1016/j.cmet.2016.05.006]</ref><ref name=”Sinclair”>Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell metabolism, 27(3), 529-547. PMID: 29514064 PMC6342515 DOI:[https://doi.org/10.1016/j.cmet.2018.02.011 10.1016/j.cmet.2018.02.011]</ref> By modulating NAD+-sensing enzymes (such as [[Sirtuins]]), NAD<sup>+</sup> controls hundreds of key processes from energy metabolism to cell survival. <ref name=”Sinclair” />		An important role in various cellular processes, including metabolism, cellular signaling, epigenetics and DNA repair plays [[NAD+\|NAD<sup>+</sup>]] (Nicotinamide adenine dinucleotide) a critical redox coenzyme. <ref name=”Chini”>Chini, C. C., Tarragó, M. G., & Chini, E. N. (2017). NAD and the aging process: Role in life, death and everything in between. Molecular and cellular endocrinology, 455, 62-74. [https://pubmed.ncbi.nlm.nih.gov/27825999/ PMID: 27825999] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419884/ PMC5419884] [https://doi.org/10.1016/j.mce.2016.11.003 doi:[https://doi.org/10.1016/j.mce.2016.11.003]</ref> <ref name=”dictates”>Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., ... & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139. PMID: 27304511 PMC4911708 DOI:[https://doi.org/10.1016/j.cmet.2016.05.006 10.1016/j.cmet.2016.05.006]</ref><ref name=”Sinclair”>Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell metabolism, 27(3), 529-547. PMID: 29514064 PMC6342515 DOI:[https://doi.org/10.1016/j.cmet.2018.02.011 10.1016/j.cmet.2018.02.011]</ref> By modulating NAD+-sensing enzymes (such as [[Sirtuins]]), NAD<sup>+</sup> controls hundreds of key processes from energy metabolism to cell survival. <ref name=”Sinclair” />

	NAD<sup>+</sup> levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. <ref name=”Chini” /><ref name=”dictates” /> <ref name=”Sinclair” /> It was shown that the enzyme CD38 is one of the main NAD-degrading enzymes in mammalian tissues.<ref name=”dictates” /><ref name=”Hogan” /> In addition to NAD<sup>+</sup>, CD38 metabolizes extracellular NAD<sup>+</sup> precursors Nicotinamide mononucleotide (NMN) and Nicotinamide riboside (NR) prior to their transport into the cell for NAD<sup>+</sup> biosynthesis.<ref name=”dictates” />		[[NAD+\|NAD<sup>+</sup>]] levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. <ref name=”Chini” /><ref name=”dictates” /> <ref name=”Sinclair” /> It was shown that the enzyme CD38 is one of the main NAD-degrading enzymes in mammalian tissues.<ref name=”dictates” /><ref name=”Hogan” /> In addition to NAD<sup>+</sup>, CD38 metabolizes extracellular NAD<sup>+</sup> precursors Nicotinamide mononucleotide (NMN) and Nicotinamide riboside (NR) prior to their transport into the cell for NAD<sup>+</sup> biosynthesis.<ref name=”dictates” />

	It was discovered that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce pro-inflammatory M1-like macrophages to proliferate and express CD38. <ref>Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., ... & Verdin, E. (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. ''Nature metabolism'', ''2''(11), 1265-1283. PMID: 33199924 PMC7908681 DOI:[https://doi.org/10.1038/s42255-020-00305-3 10.1038/s42255-020-00305-3]</ref> <ref> Chini, C., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., ... & Chini, E. N. (2020). CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. ''Nature metabolism'', ''2''(11), 1284-1304. PMID: 33199925 PMC8752031 DOI:[https://doi.org/10.1038/s42255-020-00298-z 10.1038/s42255-020-00298-z]</ref> This highlights senescent cells as an important factor in NAD<sup>+</sup> decline because the accumulation of senescent cells with age leads to increased systemic secretion of the pro-inflammatory SASP, which in turn leads to elevation of cellular CD38 expression and a concurrent decrease in NAD<sup>+</sup> levels. '''NAD<sup>+</sup> restoration has been identified as a key therapeutic target that can positively impact many of the hallmarks of cellular aging'''.<ref>Conlon, N. J. (2022). The Role of NAD+ in Regenerative Medicine. Plastic and reconstructive surgery, 150, 41S-48S. PMID:36170435 PMC9512238 DOI:[https://doi.org/10.1097/PRS.0000000000009673 10.1097/PRS.0000000000009673]</ref>		It was discovered that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce pro-inflammatory M1-like macrophages to proliferate and express CD38. <ref>Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., ... & Verdin, E. (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. ''Nature metabolism'', ''2''(11), 1265-1283. PMID: 33199924 PMC7908681 DOI:[https://doi.org/10.1038/s42255-020-00305-3 10.1038/s42255-020-00305-3]</ref> <ref> Chini, C., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., ... & Chini, E. N. (2020). CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. ''Nature metabolism'', ''2''(11), 1284-1304. PMID: 33199925 PMC8752031 DOI:[https://doi.org/10.1038/s42255-020-00298-z 10.1038/s42255-020-00298-z]</ref> This highlights senescent cells as an important factor in NAD<sup>+</sup> decline because the accumulation of senescent cells with age leads to increased systemic secretion of the pro-inflammatory SASP, which in turn leads to elevation of cellular CD38 expression and a concurrent decrease in NAD<sup>+</sup> levels. '''[[NAD+\|NAD<sup>+</sup>]] restoration has been identified as a key therapeutic target that can positively impact many of the hallmarks of cellular aging'''.<ref>Conlon, N. J. (2022). The Role of NAD+ in Regenerative Medicine. Plastic and reconstructive surgery, 150, 41S-48S. PMID:36170435 PMC9512238 DOI:[https://doi.org/10.1097/PRS.0000000000009673 10.1097/PRS.0000000000009673]</ref>
	Boosting NAD<sup>+</sup> via genetic or pharmacological CD38 targeting or NAD<sup>+</sup> precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. <ref name=”fibrosis”>Shi, B., Wang, W., Korman, B., Kai, L., Wang, Q., Wei, J., ... & Varga, J. (2021). Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis. Iscience, 24(1), 101902. PMID: 33385109 PMC7770554 DOI:[https://doi.org/10.1016/j.isci.2020.101902 10.1016/j.isci.2020.101902]</ref> Long-living-individuals (>95 years), carriers (both hetero and homozygous) of longevity-associated variant LAV-BPIFB4 gene displayed significantly higher NAD<sup>+</sup> circulating level, when compared with no-carriers, apparently due to reduction of the frequency of CD38<sup>+</sup> immune cells<ref> Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., ... & Puca, A. A. (2022). "Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline". Cell death & disease, 13(1), 1-10. PMID: 35087020 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792139 8792139] DOI:[https://doi.org/10.1038/s41419-022-04535-z 10.1038/s41419-022-04535-z]</ref> NAD<sup>+</sup> repletion with the NAD<sup>+</sup> precursor nicotinamide riboside (NR) improved mitochondrial and stem cell function and enhanced life span in mice.<ref>Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., ... & Auwerx, J. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443. PMID: 27127236 DOI:[https://doi.org/10.1126/science.aaf2693 10.1126/science.aaf2693]</ref> However, increasing NAD<sup>+</sup> using a precursor without first inhibiting CD38 may ‘fuel’ CD38-mediated inflammation due to increased secretion of pro-inflammatory tumorigenic SASP cytokines leading to elevation of cellular CD38 expression and so to repeat decrease in NAD<sup>+</sup> levels.<ref>Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., ... & Zhang, R. (2019). NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nature cell biology, 21(3), 397-407. PMID: 30778219 PMC6448588 DOI:[https://doi.org/10.1038/s41556-019-0287-4 10.1038/s41556-019-0287-4]</ref>		Boosting NAD<sup>+</sup> via genetic or pharmacological CD38 targeting or NAD<sup>+</sup> precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. <ref name=”fibrosis”>Shi, B., Wang, W., Korman, B., Kai, L., Wang, Q., Wei, J., ... & Varga, J. (2021). Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis. Iscience, 24(1), 101902. PMID: 33385109 PMC7770554 DOI:[https://doi.org/10.1016/j.isci.2020.101902 10.1016/j.isci.2020.101902]</ref> Long-living-individuals (>95 years), carriers (both hetero and homozygous) of longevity-associated variant LAV-BPIFB4 gene displayed significantly higher NAD<sup>+</sup> circulating level, when compared with no-carriers, apparently due to reduction of the frequency of CD38<sup>+</sup> immune cells<ref> Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., ... & Puca, A. A. (2022). "Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline". Cell death & disease, 13(1), 1-10. PMID: 35087020 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792139 8792139] DOI:[https://doi.org/10.1038/s41419-022-04535-z 10.1038/s41419-022-04535-z]</ref> NAD<sup>+</sup> repletion with the NAD<sup>+</sup> precursor nicotinamide riboside (NR) improved mitochondrial and stem cell function and enhanced life span in mice.<ref>Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., ... & Auwerx, J. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443. PMID: 27127236 DOI:[https://doi.org/10.1126/science.aaf2693 10.1126/science.aaf2693]</ref> However, increasing NAD<sup>+</sup> using a precursor without first inhibiting CD38 may ‘fuel’ CD38-mediated inflammation due to increased secretion of pro-inflammatory tumorigenic SASP cytokines leading to elevation of cellular CD38 expression and so to repeat decrease in NAD<sup>+</sup> levels.<ref>Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., ... & Zhang, R. (2019). NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nature cell biology, 21(3), 397-407. PMID: 30778219 PMC6448588 DOI:[https://doi.org/10.1038/s41556-019-0287-4 10.1038/s41556-019-0287-4]</ref>
	Thus, dietary NAD<sup>+</sup> augmenting supplement should be administered with precision to balance the advantageous anti-ageing effects with potential detrimental pro-tumorigenic side effects.<ref>Maric, T., Bazhin, A., Khodakivskyi, P., Mikhaylov, G., Solodnikova, E., Yevtodiyenko, A., ... & Goun, E. (2023). A bioluminescent-based probe for in vivo non-invasive monitoring of nicotinamide riboside uptake reveals a link between metastasis and NAD+ metabolism. Biosensors and Bioelectronics, 220, 114826. PMID: 36371959 DOI:[https://doi.org/10.1016/j.bios.2022.114826 10.1016/j.bios.2022.114826]</ref>		Thus, dietary NAD<sup>+</sup> augmenting supplement should be administered with precision to balance the advantageous anti-ageing effects with potential detrimental pro-tumorigenic side effects.<ref>Maric, T., Bazhin, A., Khodakivskyi, P., Mikhaylov, G., Solodnikova, E., Yevtodiyenko, A., ... & Goun, E. (2023). A bioluminescent-based probe for in vivo non-invasive monitoring of nicotinamide riboside uptake reveals a link between metastasis and NAD+ metabolism. Biosensors and Bioelectronics, 220, 114826. PMID: 36371959 DOI:[https://doi.org/10.1016/j.bios.2022.114826 10.1016/j.bios.2022.114826]</ref>

	== CD38 inhibitors ==		== CD38 inhibitors ==
	Since CD38 plays a central role in reducing the NAD<sup>+</sup> pool, artificially maintaining a high level of NAD<sup>+</sup> by inhibiting CD38 may have a positive effect on metabolic diseases and the aging.<ref name=”span”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD<sup>+</sup> decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC:5935140 doi:10.1016/j.cmet.2018.03.016</ref><ref name=”78c”>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref> Since CD38 must degrade nearly 100 molecules of NAD to generate one molecule of cADPR,<ref>Chini, E. N. (2009). CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Current pharmaceutical design, 15(1), 57-63. PMID: 19149603 PMC2883294 DOI: [https://doi.org/10.2174/138161209787185788 10.2174/138161209787185788]</ref> strategies to inhibit CD38 even at a low level may lead to substantial increases in cellular NAD+ levels.<ref>Conlon, N., & Ford, D. (2022). A systems-approach to NAD+ restoration. Biochemical pharmacology, 114946. https://doi.org/10.1016/j.bcp.2022.114946 </ref>		Since CD38 plays a central role in reducing the [[NAD+\|NAD<sup>+</sup>]] pool, artificially maintaining a high level of NAD<sup>+</sup> by inhibiting CD38 may have a positive effect on metabolic diseases and the aging.<ref name=”span”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD<sup>+</sup> decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC:5935140 doi:10.1016/j.cmet.2018.03.016</ref><ref name=”78c”>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref> Since CD38 must degrade nearly 100 molecules of NAD to generate one molecule of cADPR,<ref>Chini, E. N. (2009). CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Current pharmaceutical design, 15(1), 57-63. PMID: 19149603 PMC2883294 DOI: [https://doi.org/10.2174/138161209787185788 10.2174/138161209787185788]</ref> strategies to inhibit CD38 even at a low level may lead to substantial increases in cellular NAD+ levels.<ref>Conlon, N., & Ford, D. (2022). A systems-approach to NAD+ restoration. Biochemical pharmacology, 114946. https://doi.org/10.1016/j.bcp.2022.114946 </ref>

	The ability to inhibit CD38 have such substances as:		The ability to inhibit CD38 have such substances as:
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	Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref>		Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref>

	The potential to treat various diseases associated with NAD<sup>+</sup> deficiency without the potential side effects of small molecules and cytotoxic antibodies has an IgG (immunoglobulin) antibody '''TNB-738''' that neither crosses the cell membrane nor the blood–brain barrier. The desired mechanism of action of TNB-738 is strictly enzyme inhibition without CD38<sup>+</sup> cell depletion, thus avoiding side-effects associated with the lysis of subpopulations of immune cells, such as monocytes, effector T cells, and NK cells.<ref>Ugamraj, H. S., Dang, K., Ouisse, L. H., Buelow, B., Chini, E. N., Castello, G., ... & Dalvi, P. (2022). TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs, 14(1), 2095949 PMID:35867844 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311320 9311320] DOI:[https://doi.org/10.1080/19420862.2022.2095949 10.1080/19420862.2022.2095949] </ref>		The potential to treat various diseases associated with [[NAD+\|NAD<sup>+</sup>]] deficiency without the potential side effects of small molecules and cytotoxic antibodies has an IgG (immunoglobulin) antibody '''TNB-738''' that neither crosses the cell membrane nor the blood–brain barrier. The desired mechanism of action of TNB-738 is strictly enzyme inhibition without CD38<sup>+</sup> cell depletion, thus avoiding side-effects associated with the lysis of subpopulations of immune cells, such as monocytes, effector T cells, and NK cells.<ref>Ugamraj, H. S., Dang, K., Ouisse, L. H., Buelow, B., Chini, E. N., Castello, G., ... & Dalvi, P. (2022). TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs, 14(1), 2095949 PMID:35867844 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311320 9311320] DOI:[https://doi.org/10.1080/19420862.2022.2095949 10.1080/19420862.2022.2095949] </ref>

	== References ==		== References ==
	<references />		<references />
	[[Category:Drugs]]		[[Category:Drugs]]
	[[Category:~~Genes affecting longevity~~]]		[[Category:Main list]]
	[[Category:Longevity]]		[[Category:Longevity genes]]

Dmitry Dzhagarov: /* CD38 as a metabolic sensor and regulator */

2022-12-09T14:55:04Z

CD38 as a metabolic sensor and regulator

← Older revision		Revision as of 14:55, 9 December 2022
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	== CD38 as a metabolic sensor and regulator ==		== CD38 as a metabolic sensor and regulator ==

	An important role in various cellular processes, including metabolism, cellular signaling, epigenetics and DNA repair plays NAD<sup>+</sup> (Nicotinamide adenine dinucleotide) a critical redox coenzyme. <ref name=”Chini”>Chini, C. C., Tarragó, M. G., & Chini, E. N. (2017). NAD and the aging process: Role in life, death and everything in between. Molecular and cellular endocrinology, 455, 62-74. [https://pubmed.ncbi.nlm.nih.gov/27825999/ PMID: 27825999] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419884/ PMC5419884] [https://doi.org/10.1016/j.mce.2016.11.003 doi: 10.1016/j.mce.2016.11.003]</ref> <ref name=”dictates”>Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., ... & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139. PMID: 27304511 PMC4911708 DOI: 10.1016/j.cmet.2016.05.006</ref><ref name=”Sinclair”>Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell metabolism, 27(3), 529-547. PMID: 29514064 PMC6342515 DOI: 10.1016/j.cmet.2018.02.011</ref> By modulating NAD+-sensing enzymes (such as [[Sirtuins]]), NAD<sup>+</sup> controls hundreds of key processes from energy metabolism to cell survival. <ref name=”Sinclair” />		An important role in various cellular processes, including metabolism, cellular signaling, epigenetics and DNA repair plays NAD<sup>+</sup> (Nicotinamide adenine dinucleotide) a critical redox coenzyme. <ref name=”Chini”>Chini, C. C., Tarragó, M. G., & Chini, E. N. (2017). NAD and the aging process: Role in life, death and everything in between. Molecular and cellular endocrinology, 455, 62-74. [https://pubmed.ncbi.nlm.nih.gov/27825999/ PMID: 27825999] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419884/ PMC5419884] [https://doi.org/10.1016/j.mce.2016.11.003 doi:[https://doi.org/10.1016/j.mce.2016.11.003]</ref> <ref name=”dictates”>Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., ... & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139. PMID: 27304511 PMC4911708 DOI:[https://doi.org/10.1016/j.cmet.2016.05.006 10.1016/j.cmet.2016.05.006]</ref><ref name=”Sinclair”>Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell metabolism, 27(3), 529-547. PMID: 29514064 PMC6342515 DOI:[https://doi.org/10.1016/j.cmet.2018.02.011 10.1016/j.cmet.2018.02.011]</ref> By modulating NAD+-sensing enzymes (such as [[Sirtuins]]), NAD<sup>+</sup> controls hundreds of key processes from energy metabolism to cell survival. <ref name=”Sinclair” />

	NAD<sup>+</sup> levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. <ref name=”Chini” /><ref name=”dictates” /> <ref name=”Sinclair” /> It was shown that the enzyme CD38 is one of the main NAD-degrading enzymes in mammalian tissues.<ref name=”dictates” /><ref name=”Hogan” /> In addition to NAD<sup>+</sup>, CD38 metabolizes extracellular NAD<sup>+</sup> precursors Nicotinamide mononucleotide (NMN) and Nicotinamide riboside (NR) prior to their transport into the cell for NAD<sup>+</sup> biosynthesis.<ref name=”dictates” />		NAD<sup>+</sup> levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. <ref name=”Chini” /><ref name=”dictates” /> <ref name=”Sinclair” /> It was shown that the enzyme CD38 is one of the main NAD-degrading enzymes in mammalian tissues.<ref name=”dictates” /><ref name=”Hogan” /> In addition to NAD<sup>+</sup>, CD38 metabolizes extracellular NAD<sup>+</sup> precursors Nicotinamide mononucleotide (NMN) and Nicotinamide riboside (NR) prior to their transport into the cell for NAD<sup>+</sup> biosynthesis.<ref name=”dictates” />

	It was discovered that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce pro-inflammatory M1-like macrophages to proliferate and express CD38. <ref>Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., ... & Verdin, E. (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. ''Nature metabolism'', ''2''(11), 1265-1283. PMID: 33199924 PMC7908681 DOI: 10.1038/s42255-020-00305-3</ref> <ref> Chini, C., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., ... & Chini, E. N. (2020). CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. ''Nature metabolism'', ''2''(11), 1284-1304. PMID: 33199925 PMC8752031 DOI: 10.1038/s42255-020-00298-z</ref> This highlights senescent cells as an important factor in NAD<sup>+</sup> decline because the accumulation of senescent cells with age leads to increased systemic secretion of the pro-inflammatory SASP, which in turn leads to elevation of cellular CD38 expression and a concurrent decrease in NAD<sup>+</sup> levels. '''NAD<sup>+</sup> restoration has been identified as a key therapeutic target that can positively impact many of the hallmarks of cellular aging'''.<ref>Conlon, N. J. (2022). The Role of NAD+ in Regenerative Medicine. Plastic and reconstructive surgery, 150, 41S-48S. PMID:36170435 PMC9512238 DOI: 10.1097/PRS.0000000000009673</ref>		It was discovered that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce pro-inflammatory M1-like macrophages to proliferate and express CD38. <ref>Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., ... & Verdin, E. (2020). Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. ''Nature metabolism'', ''2''(11), 1265-1283. PMID: 33199924 PMC7908681 DOI:[https://doi.org/10.1038/s42255-020-00305-3 10.1038/s42255-020-00305-3]</ref> <ref> Chini, C., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., ... & Chini, E. N. (2020). CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. ''Nature metabolism'', ''2''(11), 1284-1304. PMID: 33199925 PMC8752031 DOI:[https://doi.org/10.1038/s42255-020-00298-z 10.1038/s42255-020-00298-z]</ref> This highlights senescent cells as an important factor in NAD<sup>+</sup> decline because the accumulation of senescent cells with age leads to increased systemic secretion of the pro-inflammatory SASP, which in turn leads to elevation of cellular CD38 expression and a concurrent decrease in NAD<sup>+</sup> levels. '''NAD<sup>+</sup> restoration has been identified as a key therapeutic target that can positively impact many of the hallmarks of cellular aging'''.<ref>Conlon, N. J. (2022). The Role of NAD+ in Regenerative Medicine. Plastic and reconstructive surgery, 150, 41S-48S. PMID:36170435 PMC9512238 DOI:[https://doi.org/10.1097/PRS.0000000000009673 10.1097/PRS.0000000000009673]</ref>
	Boosting NAD<sup>+</sup> via genetic or pharmacological CD38 targeting or NAD<sup>+</sup> precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. <ref name=”fibrosis”>Shi, B., Wang, W., Korman, B., Kai, L., Wang, Q., Wei, J., ... & Varga, J. (2021). Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis. Iscience, 24(1), 101902. PMID: 33385109 PMC7770554 DOI: 10.1016/j.isci.2020.101902</ref> Long-living-individuals (>95 years), carriers (both hetero and homozygous) of longevity-associated variant LAV-BPIFB4 gene displayed significantly higher NAD<sup>+</sup> circulating level, when compared with no-carriers, apparently due to reduction of the frequency of CD38<sup>+</sup> immune cells<ref> Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., ... & Puca, A. A. (2022). "Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline". Cell death & disease, 13(1), 1-10. PMID: 35087020 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792139 8792139] DOI: 10.1038/s41419-022-04535-z</ref> NAD<sup>+</sup> repletion with the NAD<sup>+</sup> precursor nicotinamide riboside (NR) improved mitochondrial and stem cell function and enhanced life span in mice.<ref>Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., ... & Auwerx, J. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443. PMID: 27127236 DOI: 10.1126/science.aaf2693</ref> However, increasing NAD<sup>+</sup> using a precursor without first inhibiting CD38 may ‘fuel’ CD38-mediated inflammation due to increased secretion of pro-inflammatory tumorigenic SASP cytokines leading to elevation of cellular CD38 expression and so to repeat decrease in NAD<sup>+</sup> levels.<ref>Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., ... & Zhang, R. (2019). NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nature cell biology, 21(3), 397-407. PMID: 30778219 PMC6448588 DOI: 10.1038/s41556-019-0287-4</ref>		Boosting NAD<sup>+</sup> via genetic or pharmacological CD38 targeting or NAD<sup>+</sup> precursor supplementation protected mice from skin, lung, and peritoneal fibrosis. <ref name=”fibrosis”>Shi, B., Wang, W., Korman, B., Kai, L., Wang, Q., Wei, J., ... & Varga, J. (2021). Targeting CD38-dependent NAD+ metabolism to mitigate multiple organ fibrosis. Iscience, 24(1), 101902. PMID: 33385109 PMC7770554 DOI:[https://doi.org/10.1016/j.isci.2020.101902 10.1016/j.isci.2020.101902]</ref> Long-living-individuals (>95 years), carriers (both hetero and homozygous) of longevity-associated variant LAV-BPIFB4 gene displayed significantly higher NAD<sup>+</sup> circulating level, when compared with no-carriers, apparently due to reduction of the frequency of CD38<sup>+</sup> immune cells<ref> Ciaglia, E., Lopardo, V., Montella, F., Carrizzo, A., Di Pietro, P., Malavolta, M., ... & Puca, A. A. (2022). "Transfer of the longevity-associated variant of BPIFB4 gene rejuvenates immune system and vasculature by a reduction of CD38+ macrophages and NAD+ decline". Cell death & disease, 13(1), 1-10. PMID: 35087020 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792139 8792139] DOI:[https://doi.org/10.1038/s41419-022-04535-z 10.1038/s41419-022-04535-z]</ref> NAD<sup>+</sup> repletion with the NAD<sup>+</sup> precursor nicotinamide riboside (NR) improved mitochondrial and stem cell function and enhanced life span in mice.<ref>Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., ... & Auwerx, J. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443. PMID: 27127236 DOI:[https://doi.org/10.1126/science.aaf2693 10.1126/science.aaf2693]</ref> However, increasing NAD<sup>+</sup> using a precursor without first inhibiting CD38 may ‘fuel’ CD38-mediated inflammation due to increased secretion of pro-inflammatory tumorigenic SASP cytokines leading to elevation of cellular CD38 expression and so to repeat decrease in NAD<sup>+</sup> levels.<ref>Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., ... & Zhang, R. (2019). NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nature cell biology, 21(3), 397-407. PMID: 30778219 PMC6448588 DOI:[https://doi.org/10.1038/s41556-019-0287-4 10.1038/s41556-019-0287-4]</ref>
	Thus, dietary NAD<sup>+</sup> augmenting supplement should be administered with precision to balance the advantageous anti-ageing effects with potential detrimental pro-tumorigenic side effects.		Thus, dietary NAD<sup>+</sup> augmenting supplement should be administered with precision to balance the advantageous anti-ageing effects with potential detrimental pro-tumorigenic side effects.<ref>Maric, T., Bazhin, A., Khodakivskyi, P., Mikhaylov, G., Solodnikova, E., Yevtodiyenko, A., ... & Goun, E. (2023). A bioluminescent-based probe for in vivo non-invasive monitoring of nicotinamide riboside uptake reveals a link between metastasis and NAD+ metabolism. Biosensors and Bioelectronics, 220, 114826. PMID: 36371959 DOI:[https://doi.org/10.1016/j.bios.2022.114826 10.1016/j.bios.2022.114826]</ref>

	== CD38 inhibitors ==		== CD38 inhibitors ==

Andrea: /* added category */

2022-11-18T15:46:49Z

added category

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	Anthocyanins, such as luteolinidin, protects endothelial and myocardial function in the postischemic heart through CD38 inhibition.<ref> Boslett, J., Hemann, C., Zhao, Y. J., Lee, H. C., & Zweier, J. L. (2017). Luteolinidin protects the postischemic heart through CD38 inhibition with preservation of NAD (P)(H). Journal of Pharmacology and Experimental Therapeutics, 361(1), 99-108. PMID: 28108596 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363772 5363772] DOI: 10.1124/jpet.116.239459</ref>		Anthocyanins, such as luteolinidin, protects endothelial and myocardial function in the postischemic heart through CD38 inhibition.<ref> Boslett, J., Hemann, C., Zhao, Y. J., Lee, H. C., & Zweier, J. L. (2017). Luteolinidin protects the postischemic heart through CD38 inhibition with preservation of NAD (P)(H). Journal of Pharmacology and Experimental Therapeutics, 361(1), 99-108. PMID: 28108596 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363772 5363772] DOI: 10.1124/jpet.116.239459</ref>

	In diseases associated with aging, for therapy that increases NAD<sup>+</sup> can be used a '''78c''' inhibitor.<ref>Chini, E. N., Chini, C. C., Netto, J. M. E., de Oliveira, G. C., & van Schooten, W. (2018). The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in pharmacological sciences, 39(4), 424-436. PMID:29482842 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288 5885288] doi:10.1016/j.tips.2018.02.001</ref><ref name=”Tarragó”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140 5935140] doi:10.1016/j.cmet.2018.03.016</ref> For example, 78c increased the level of NAD in the liver by 536% just two hours after ingestion.<ref>Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. C. (2015). Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors. Journal of medicinal chemistry, 58(8), 3548-3571. PMID 25828863 doi:10.1021/jm502009h</ref> Treatment of old mice with the NADase 78c inhibitor markedly reduced the accumulation of inflammatory cells in tissues and significantly reduced the appearance of fibrotic and inflammatory changes with aging in muscles <ref name=”Tarragó” /> , as well as in the skin, lungs and peritoneal mucosa.<ref name=”fibrosis” /> In in vitro experiments on mouse hearts, treatment with 78c significantly reduced the effects of myocardial infarction.<ref>Boslett, J., Reddy, N., Alzarie, Y. A., & Zweier, J. L. (2019). Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury. Journal of Pharmacology and Experimental Therapeutics, 369(1), 55-64. PMID 30635470 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413770 6413770] doi:10.1124/jpet.118.254557</ref>		In diseases associated with aging, for therapy that increases NAD<sup>+</sup> can be used a '''78c''' inhibitor.<ref>Chini, E. N., Chini, C. C., Netto, J. M. E., de Oliveira, G. C., & van Schooten, W. (2018). The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in pharmacological sciences, 39(4), 424-436. PMID:29482842 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288 5885288] doi:10.1016/j.tips.2018.02.001</ref><ref name=”Tarragó”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140 5935140] doi:10.1016/j.cmet.2018.03.016</ref> For example, 78c increased the level of NAD in the liver by 536% just two hours after ingestion.<ref>Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. C. (2015). Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors. Journal of medicinal chemistry, 58(8), 3548-3571. PMID 25828863 doi:10.1021/jm502009h</ref> Treatment of old mice with the NADase 78c inhibitor markedly reduced the accumulation of inflammatory cells in tissues and significantly reduced the appearance of fibrotic and inflammatory changes with aging in muscles <ref name=”Tarragó” /> , as well as in the skin, lungs and peritoneal mucosa.<ref name=”fibrosis” /> In in vitro experiments on mouse hearts, treatment with 78c significantly reduced the effects of myocardial infarction.<ref>Boslett, J., Reddy, N., Alzarie, Y. A., & Zweier, J. L. (2019). Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury. Journal of Pharmacology and Experimental Therapeutics, 369(1), 55-64. PMID 30635470 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413770 6413770] doi:10.1124/jpet.118.254557</ref>[[File:TNB-738-mediated CD38 inhibition.jpg\|thumb\|Intracellular NAD+ boosting by TNB-738-mediated CD38 inhibition (Ugamraj et al., 2022)]]

	'''78c has been shown to increase lifespan (average by 17% and maximal by 14%)''' and protect against aging-induced health loss in aged male mice.<ref>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref>		'''78c has been shown to increase lifespan (average by 17% and maximal by 14%)''' and protect against aging-induced health loss in aged male mice.<ref>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref>
	~~[[File:TNB-738-mediated CD38 inhibition.jpg\|thumb\|Intracellular NAD+ boosting by TNB-738-mediated CD38 inhibition (Ugamraj et al., 2022)]]~~

	Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref>		Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref>
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	[[Category:Genes affecting longevity]]		[[Category:Genes affecting longevity]]
			[[Category:Longevity]]

Dmitry Dzhagarov: /* References */

2022-11-18T09:17:10Z

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Dmitry Dzhagarov: /* References */

2022-11-18T09:15:40Z

References

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Dmitry Dzhagarov: /* CD38 inhibitors */

2022-11-10T09:01:39Z

CD38 inhibitors

← Older revision		Revision as of 09:01, 10 November 2022
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	In diseases associated with aging, for therapy that increases NAD<sup>+</sup> can be used a '''78c''' inhibitor.<ref>Chini, E. N., Chini, C. C., Netto, J. M. E., de Oliveira, G. C., & van Schooten, W. (2018). The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in pharmacological sciences, 39(4), 424-436. PMID:29482842 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288 5885288] doi:10.1016/j.tips.2018.02.001</ref><ref name=”Tarragó”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140 5935140] doi:10.1016/j.cmet.2018.03.016</ref> For example, 78c increased the level of NAD in the liver by 536% just two hours after ingestion.<ref>Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. C. (2015). Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors. Journal of medicinal chemistry, 58(8), 3548-3571. PMID 25828863 doi:10.1021/jm502009h</ref> Treatment of old mice with the NADase 78c inhibitor markedly reduced the accumulation of inflammatory cells in tissues and significantly reduced the appearance of fibrotic and inflammatory changes with aging in muscles <ref name=”Tarragó” /> , as well as in the skin, lungs and peritoneal mucosa.<ref name=”fibrosis” /> In in vitro experiments on mouse hearts, treatment with 78c significantly reduced the effects of myocardial infarction.<ref>Boslett, J., Reddy, N., Alzarie, Y. A., & Zweier, J. L. (2019). Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury. Journal of Pharmacology and Experimental Therapeutics, 369(1), 55-64. PMID 30635470 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413770 6413770] doi:10.1124/jpet.118.254557</ref>		In diseases associated with aging, for therapy that increases NAD<sup>+</sup> can be used a '''78c''' inhibitor.<ref>Chini, E. N., Chini, C. C., Netto, J. M. E., de Oliveira, G. C., & van Schooten, W. (2018). The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in pharmacological sciences, 39(4), 424-436. PMID:29482842 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288 5885288] doi:10.1016/j.tips.2018.02.001</ref><ref name=”Tarragó”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140 5935140] doi:10.1016/j.cmet.2018.03.016</ref> For example, 78c increased the level of NAD in the liver by 536% just two hours after ingestion.<ref>Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. C. (2015). Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors. Journal of medicinal chemistry, 58(8), 3548-3571. PMID 25828863 doi:10.1021/jm502009h</ref> Treatment of old mice with the NADase 78c inhibitor markedly reduced the accumulation of inflammatory cells in tissues and significantly reduced the appearance of fibrotic and inflammatory changes with aging in muscles <ref name=”Tarragó” /> , as well as in the skin, lungs and peritoneal mucosa.<ref name=”fibrosis” /> In in vitro experiments on mouse hearts, treatment with 78c significantly reduced the effects of myocardial infarction.<ref>Boslett, J., Reddy, N., Alzarie, Y. A., & Zweier, J. L. (2019). Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury. Journal of Pharmacology and Experimental Therapeutics, 369(1), 55-64. PMID 30635470 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413770 6413770] doi:10.1124/jpet.118.254557</ref>

	'''78c has been shown to increase lifespan (average by 17% and maximal by 14%)''' and protect against aging-induced health loss in aged male mice.<ref>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref>		'''78c has been shown to increase lifespan (average by 17% and maximal by 14%)''' and protect against aging-induced health loss in aged male mice.<ref>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref>
			[[File:TNB-738-mediated CD38 inhibition.jpg\|thumb\|Intracellular NAD+ boosting by TNB-738-mediated CD38 inhibition (Ugamraj et al., 2022)]]

	Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref>		Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref>

	The potential to treat various diseases associated with NAD<sup>+</sup> deficiency without the potential side effects of small molecules and cytotoxic antibodies has an IgG (immunoglobulin) antibody '''TNB-738''' that neither crosses the cell membrane nor the blood–brain barrier. The desired mechanism of action of TNB-738 is strictly enzyme inhibition without CD38<sup>+</sup> cell depletion, thus avoiding side-effects associated with the lysis of subpopulations of immune cells, such as monocytes, effector T cells, and NK cells.<ref>Ugamraj, H. S., Dang, K., Ouisse, L. H., Buelow, B., Chini, E. N., Castello, G., ... & Dalvi, P. (2022). TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs, 14(1), 2095949 PMID:35867844 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311320 9311320] DOI:[https://doi.org/10.1080/19420862.2022.2095949 10.1080/19420862.2022.2095949] </ref>		The potential to treat various diseases associated with NAD<sup>+</sup> deficiency without the potential side effects of small molecules and cytotoxic antibodies has an IgG (immunoglobulin) antibody '''TNB-738''' that neither crosses the cell membrane nor the blood–brain barrier. The desired mechanism of action of TNB-738 is strictly enzyme inhibition without CD38<sup>+</sup> cell depletion, thus avoiding side-effects associated with the lysis of subpopulations of immune cells, such as monocytes, effector T cells, and NK cells.<ref>Ugamraj, H. S., Dang, K., Ouisse, L. H., Buelow, B., Chini, E. N., Castello, G., ... & Dalvi, P. (2022). TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs, 14(1), 2095949 PMID:35867844 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311320 9311320] DOI:[https://doi.org/10.1080/19420862.2022.2095949 10.1080/19420862.2022.2095949] </ref>

← Older revision		Revision as of 20:55, 20 September 2023
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	== CD38 inhibitors ==		== CD38 inhibitors ==
	Since CD38 plays a central role in reducing the [[NAD+\|NAD<sup>+</sup>]] pool, artificially maintaining a high level of NAD<sup>+</sup> by inhibiting CD38 may have a positive effect on metabolic diseases and the aging.<ref name=”span”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD<sup>+</sup> decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC:5935140 doi:10.1016/j.cmet.2018.03.016</ref><ref name=”78c”>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref> Since CD38 must degrade nearly 100 molecules of NAD to generate one molecule of cADPR,<ref>Chini, E. N. (2009). CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Current pharmaceutical design, 15(1), 57-63. PMID: 19149603 PMC2883294 DOI: [https://doi.org/10.2174/138161209787185788 10.2174/138161209787185788]</ref> strategies to inhibit CD38 even at a low level may lead to substantial increases in cellular NAD+ levels.<ref>Conlon, N., & Ford, D. (2022). A systems-approach to NAD+ restoration. Biochemical pharmacology, 114946. https://doi.org/10.1016/j.bcp.2022.114946 </ref>		Since CD38 plays a central role in reducing the [[NAD+\|NAD<sup>+</sup>]] pool, artificially maintaining a high level of NAD<sup>+</sup> by inhibiting CD38 may have a positive effect on metabolic diseases and the aging.<ref name=”span”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD<sup>+</sup> decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC:5935140 doi:10.1016/j.cmet.2018.03.016</ref><ref name=”78c”>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref> Since CD38 must degrade nearly 100 molecules of NAD to generate one molecule of cADPR,<ref>Chini, E. N. (2009). CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Current pharmaceutical design, 15(1), 57-63. PMID: 19149603 PMC2883294 DOI: [https://doi.org/10.2174/138161209787185788 10.2174/138161209787185788]</ref> strategies to inhibit CD38 even at a low level may lead to substantial increases in cellular NAD<sup>+</sup> levels.<ref>Conlon, N., & Ford, D. (2022). A systems-approach to NAD<sup>+</sup> restoration. Biochemical pharmacology, 114946. https://doi.org/10.1016/j.bcp.2022.114946 </ref>

	The ability to inhibit CD38 have such substances as:		The ability to inhibit CD38 have such substances as:
	Flavonoids<ref>Kellenberger, E., Kuhn, I., Schuber, F., & Muller-Steffner, H. (2011). Flavonoids as inhibitors of human CD38. Bioorganic & medicinal chemistry letters, 21(13), 3939-3942. PMID: 21641214 DOI: 10.1016/j.bmcl.2011.05.022</ref> (in particular '''apigenin'''.<ref>Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., ... & Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62(4), 1084-1093. </ref> The reason for which it is useful to eat celery (''Apium graveolens''), parsley and radish leaves - they are source of apigenin.<ref> Li, Z., Zhou, J., Ji, L., Liang, Y., & Xie, S. (2022). Recent Advances in the Pharmacological Actions of Apigenin, Its Complexes, and Its Derivatives. Food Reviews International, 1-34. https://doi.org/10.1080/87559129.2022.2122989</ref>).		Flavonoids<ref>Kellenberger, E., Kuhn, I., Schuber, F., & Muller-Steffner, H. (2011). Flavonoids as inhibitors of human CD38. Bioorganic & medicinal chemistry letters, 21(13), 3939-3942. PMID: 21641214 DOI: 10.1016/j.bmcl.2011.05.022</ref> (in particular '''apigenin'''.<ref>Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., ... & Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the NAD<sup>+</sup> ase CD38: implications for cellular NAD<sup>+</sup> metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62(4), 1084-1093. </ref> The reason for which it is useful to eat celery (''Apium graveolens''), parsley and radish leaves - they are source of apigenin.<ref> Li, Z., Zhou, J., Ji, L., Liang, Y., & Xie, S. (2022). Recent Advances in the Pharmacological Actions of Apigenin, Its Complexes, and Its Derivatives. Food Reviews International, 1-34. https://doi.org/10.1080/87559129.2022.2122989</ref>).

	Anthocyanins, such as luteolinidin, protects endothelial and myocardial function in the postischemic heart through CD38 inhibition.<ref> Boslett, J., Hemann, C., Zhao, Y. J., Lee, H. C., & Zweier, J. L. (2017). Luteolinidin protects the postischemic heart through CD38 inhibition with preservation of NAD (P)(H). Journal of Pharmacology and Experimental Therapeutics, 361(1), 99-108. PMID: 28108596 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363772 5363772] DOI: 10.1124/jpet.116.239459</ref>		Anthocyanins, such as luteolinidin, protects endothelial and myocardial function in the postischemic heart through CD38 inhibition.<ref> Boslett, J., Hemann, C., Zhao, Y. J., Lee, H. C., & Zweier, J. L. (2017). Luteolinidin protects the postischemic heart through CD38 inhibition with preservation of NAD (P)(H). Journal of Pharmacology and Experimental Therapeutics, 361(1), 99-108. PMID: 28108596 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363772 5363772] DOI: 10.1124/jpet.116.239459</ref>
	[[File:CD38 inhibitor 78c.jpg\|thumb\|Potent CD38 inhibitor '''78c''', can act ''in vivo''.]]		[[File:CD38 inhibitor 78c.jpg\|thumb\|Potent CD38 inhibitor '''78c''', can act ''in vivo''.]]
	In diseases associated with aging, for therapy that increases NAD<sup>+</sup> can be used a '''78c''' inhibitor.<ref>Chini, E. N., Chini, C. C., Netto, J. M. E., de Oliveira, G. C., & van Schooten, W. (2018). The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in pharmacological sciences, 39(4), 424-436. PMID:29482842 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288 5885288] doi:10.1016/j.tips.2018.02.001</ref><ref name=”Tarragó”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140 5935140] doi:10.1016/j.cmet.2018.03.016</ref> For example, 78c increased the level of NAD in the liver by 536% just two hours after ingestion.<ref>Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. C. (2015). Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors. Journal of medicinal chemistry, 58(8), 3548-3571. PMID 25828863 doi:10.1021/jm502009h</ref> Treatment of old mice with the NADase 78c inhibitor markedly reduced the accumulation of inflammatory cells in tissues and significantly reduced the appearance of fibrotic and inflammatory changes with aging in muscles <ref name=”Tarragó” /> , as well as in the skin, lungs and peritoneal mucosa.<ref name=”fibrosis” /> In in vitro experiments on mouse hearts, treatment with 78c significantly reduced the effects of myocardial infarction.<ref>Boslett, J., Reddy, N., Alzarie, Y. A., & Zweier, J. L. (2019). Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury. Journal of Pharmacology and Experimental Therapeutics, 369(1), 55-64. PMID 30635470 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413770 6413770] doi:10.1124/jpet.118.254557</ref>[[File:TNB-738-mediated CD38 inhibition.jpg\|thumb\|Intracellular NAD+ boosting by TNB-738-mediated CD38 inhibition (Ugamraj et al., 2022)]]		In diseases associated with aging, for therapy that increases NAD<sup>+</sup> can be used a '''78c''' inhibitor.<ref>Chini, E. N., Chini, C. C., Netto, J. M. E., de Oliveira, G. C., & van Schooten, W. (2018). The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in pharmacological sciences, 39(4), 424-436. PMID:29482842 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885288 5885288] doi:10.1016/j.tips.2018.02.001</ref><ref name=”Tarragó”>Tarragó, M. G., Chini, C. C., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., ... & Chini, E. N. (2018). A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell metabolism, 27(5), 1081-1095. PMID:29719225 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935140 5935140] doi:10.1016/j.cmet.2018.03.016</ref> For example, 78c increased the level of NAD<sup>+</sup> in the liver by 536% just two hours after ingestion.<ref>Haffner, C. D., Becherer, J. D., Boros, E. E., Cadilla, R., Carpenter, T., Cowan, D., ... & Ulrich, J. C. (2015). Discovery, synthesis, and biological evaluation of thiazoloquin (az) olin (on) es as potent CD38 inhibitors. Journal of medicinal chemistry, 58(8), 3548-3571. PMID 25828863 doi:10.1021/jm502009h</ref> Treatment of old mice with the NADase 78c inhibitor markedly reduced the accumulation of inflammatory cells in tissues and significantly reduced the appearance of fibrotic and inflammatory changes with aging in muscles <ref name=”Tarragó” /> , as well as in the skin, lungs and peritoneal mucosa.<ref name=”fibrosis” /> In in vitro experiments on mouse hearts, treatment with 78c significantly reduced the effects of myocardial infarction.<ref>Boslett, J., Reddy, N., Alzarie, Y. A., & Zweier, J. L. (2019). Inhibition of CD38 with the Thiazoloquin (az) olin (on) e 78c Protects the Heart against Postischemic Injury. Journal of Pharmacology and Experimental Therapeutics, 369(1), 55-64. PMID 30635470 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413770 6413770] doi:10.1124/jpet.118.254557</ref>[[File:TNB-738-mediated CD38 inhibition.jpg\|thumb\|Intracellular NAD<sup>+</sup> boosting by TNB-738-mediated CD38 inhibition (Ugamraj et al., 2022)]]

	'''78c has been shown to increase lifespan (average by 17% and maximal by 14%)''' and protect against aging-induced health loss in aged male mice.<ref>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref>		'''78c has been shown to increase lifespan (average by 17% and maximal by 14%)''' and protect against aging-induced health loss in aged male mice.<ref>Peclat, T. R., Thompson, K. L., Warner, G. M., Chini, C. C., Tarragó, M. G., Mazdeh, D. Z., ... & Chini, E. N. (2022). CD38 inhibitor 78c increases mice lifespan and healthspan in a model of chronological aging. Aging Cell, e13589. PMID:35263032 [https://doi.org/10.1111/acel.13589 doi:10.1111/acel.13589]</ref>
			[[File:Компонент I.jpg\|thumb\|A CD38 inhibitor called compound 1 developed by Li et al.<ref name="Mitoch">Li, Y., Liu, Y., Zhang, Y., Wu, Y., Xing, Z., Wang, J., & Fan, G. H. (2023). Discovery of a First-in-Class CD38 Inhibitor for the Treatment of Mitochondrial Myopathy. Journal of Medicinal Chemistry. PMID:37696000 [https://doi.org/10.1021/acs.jmedchem.3c00391 DOI:10.1021/acs.jmedchem.3c00391]</ref>]]
	Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref> Administration of the CD38 inhibitor MK-0159 reverses mitochondrial defects and restores CD8+ T cells function against infections in mice and so substantially improves the pathology linked to viral infection.<ref>Chen, P. M., Katsuyama, E., Satyam, A., Li, H., Rubio, J., Jung, S., ... & Tsokos, G. C. (2022). CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy. Science Advances, 8(24), eabo4271. PMID: 35704572 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9200274 9200274] DOI: 10.1126/sciadv.abo4271</ref>		Orally bioavailable enzymatic inhibitor of CD38, '''MK-0159''' in experiments with mice show strong protection from myocardial damage upon cardiac ischemia/reperfusion injury in the murine heart.<ref>Lagu, B., Wu, X., Kulkarni, S., Paul, R., Becherer, J. D., Olson, L., ... & Andrzejewski, S. (2022). Orally Bioavailable Enzymatic Inhibitor of CD38, MK-0159, Protects against Ischemia/Reperfusion Injury in the Murine Heart. Journal of medicinal chemistry, 65(13), 9418-9446. PMID:35762533 [https://doi.org/10.1021/acs.jmedchem.2c00688 DOI:10.1021/acs.jmedchem.2c00688]</ref> Administration of the CD38 inhibitor MK-0159 reverses mitochondrial defects and restores CD8+ T cells function against infections in mice and so substantially improves the pathology linked to viral infection.<ref>Chen, P. M., Katsuyama, E., Satyam, A., Li, H., Rubio, J., Jung, S., ... & Tsokos, G. C. (2022). CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy. Science Advances, 8(24), eabo4271. PMID: 35704572 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9200274 9200274] DOI: 10.1126/sciadv.abo4271</ref>

	The potential to treat various diseases associated with [[NAD+\|NAD<sup>+</sup>]] deficiency without the potential side effects of small molecules and cytotoxic antibodies has an IgG (immunoglobulin) antibody '''TNB-738''' that neither crosses the cell membrane nor the blood–brain barrier. The desired mechanism of action of TNB-738 is strictly enzyme inhibition without CD38<sup>+</sup> cell depletion, thus avoiding side-effects associated with the lysis of subpopulations of immune cells, such as monocytes, effector T cells, and NK cells.<ref>Ugamraj, H. S., Dang, K., Ouisse, L. H., Buelow, B., Chini, E. N., Castello, G., ... & Dalvi, P. (2022). TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs, 14(1), 2095949 PMID:35867844 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311320 9311320] DOI:[https://doi.org/10.1080/19420862.2022.2095949 10.1080/19420862.2022.2095949] </ref>		The potential to treat various diseases associated with [[NAD+\|NAD<sup>+</sup>]] deficiency without the potential side effects of small molecules and cytotoxic antibodies has an IgG (immunoglobulin) antibody '''TNB-738''' that neither crosses the cell membrane nor the blood–brain barrier. The desired mechanism of action of TNB-738 is strictly enzyme inhibition without CD38<sup>+</sup> cell depletion, thus avoiding side-effects associated with the lysis of subpopulations of immune cells, such as monocytes, effector T cells, and NK cells.<ref>Ugamraj, H. S., Dang, K., Ouisse, L. H., Buelow, B., Chini, E. N., Castello, G., ... & Dalvi, P. (2022). TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs, 14(1), 2095949 PMID:35867844 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311320 9311320] DOI:[https://doi.org/10.1080/19420862.2022.2095949 10.1080/19420862.2022.2095949] </ref>

			The promising candidate for its excellent in vivo efficacy, favorable pharmacokinetics, and attractive safety profile, called '''compound 1''' has a great effect on mitochondrial function, metabolic processes, muscle contraction/development, and actin filament organization via regulating the expression of relevant genes associated with an elevated NAD<sup>+</sup> level.<ref name="Mitoch"/>

	== References ==		== References ==