Metadichol®-induced expression of circadian clock transcription factors in human fibroblasts
Main Article Content
Abstract
Circadian clock genes regulate many physiological processes, including sleep, metabolism, inflammation, and cancer. Disruptions in these cycles are associated with heightened vulnerability to cancer, psychiatric diseases, and neurological problems. Circadian clock genes play a vital role in the growth and progression of cancer. Manipulating the circadian clock mechanism can eliminate cancer cells, augment the effectiveness of chemotherapy, eliminate senescent cells, and reinstate regular circadian cycles.
The circadian clock genes that are crucial for regulating the daily physiological processes of mammals include Cry1, Bmal1, Per1, Ppargc1a, and Clock. Currently, there is a lack of information regarding small molecules that can effectively control and activate all five transcription factors. By subjecting fibroblasts to treatment with Metadichol, we can induce the expression of all the genes, as evidenced by the results obtained from quantitative real-time polymerase chain reaction (qRT‒PCR). The administration of metadichol significantly enhanced the expression of the Cry1, Clock, and Ppargc1a genes in human fibroblasts, resulting in a four- to fivefold increase in expression. Metadichol successfully maintained the expression of the Per1 and Bmal1 genes at a dose of 100 ng. Clock and Bmal1 heterodimers initiate the activation of Cry1, Per1, and other clock genes via a feedback loop. The Cry1 and Per1 proteins inhibit the function of Clock-Bmal1. Ppargc1a regulates the expression of Clock and metabolic genes. Metadichol did not result in elevated levels of Per1 and Bmal1 expression, suggesting that it does not directly affect these genes. Metadichol is a nontoxic molecule, and its effects on circadian rhythm can have significant implications for human health to alleviate the progression of numerous ailments and diseases
Keywords:
Circadian rhythm, Clock, Bmal1, Per1, Cry1, Ppargc1a, NRID1, Metadichol, Nanoemulsion, Long-Chain Alcohols, Sirt 1 and Sirt 6
Article Details
How to Cite
RAGHAVAN, P.R..
Metadichol®-induced expression of circadian clock transcription factors in human fibroblasts.
Medical Research Archives, [S.l.], v. 12, n. 6, june 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5371>. Date accessed: 02 july 2024.
doi: https://doi.org/10.18103/mra.v12i6.5371.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Circadian Rhythms; https://www.nigms.nih.gov/education/fact-sheets/Pages/circadian-rhythms.aspx
2. Physiology; Circadian rhythms. https://www.ncbi.nlm.nih.gov/books/NBK519507/
3. Rijo-Ferreira, F., Takahashi, J.S. Genomics of cir¬cadian rhythms in health and disease. Genome Med, 2019; 11, 82 https://doi.org/10.1186/s13073-019-0704-0.
4. Trott AJ, Menet JS. Regulation of circadian clock transcriptional output by CLOCK:BMAL1. PLoS Genet. 2018; Jan 4;14(1):e1007156. Doi: 10.1371/journal.pgen.1007156.
5. Alex A Koch ,et al. 2022. Quantification of pro¬tein abundance and interaction defines a mech¬anism for operation of the circadian clock eLife 11:e73976. https://doi.org/10.7554/eLife.73976.
6. Kawai M, Rosen CJ. PPARγ: a circadian tran-scription factor in adipogenesis and osteogene-sis. Nat Rev Endocrinol. 2010 ;Nov;6(11):629-36. Doi: 10.1038/nrendo.2010.155.
7. Liu H, Liu Y, Hai R, Liao W, Luo X. The role of circadian clocks in cancer: Mechanisms and clini¬cal implications. Genes Dis. 2022; May 28;10 (4):1279-1290. Doi: 10.1016/j.gen-dis.2022. 05.014.
8. Zhang W, Xiong Y, Tao R, Panayi AC, Mi B, Liu G. Emerging Insight into the Role of Circadian Clock Gene BMAL1 in Cellular Senescence. Front Endocrinol (Lausanne). 2022; Jun 6;13:915139. Doi: 10.3389/fendo.2022.915139.
9. Yanling Xie Front. Physiol., 2019; New Insights into the Circadian Rhythm and Its Related Dis-eases Sec. Chronobiology Volume 10. | https://doi.org/10.3389/fphys.2019.00682.
10. Walker, W.H., Walton, J.C., DeVries, A.C. et al. Circadian rhythm disruption and mental health. Transl Psychiatry, 2020; 10, 28. https://doi.org/10.1038/s41398-020-0694-0.
11. A Zhang W, Xiong Y, Tao R, Panayi AC, Mi B, Liu G. Emerging Insight into the Role of Circadian Clock Gene BMAL1 in Cellular Senescence. Front Endocrinol (Lausanne). 2022; Jun 6;13:915139. Doi: 10.3389/fendo.2022.915139.
12. Vadnie CA, McClung CA. Circadian Rhythm Dis-turbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus. Neural Plast. 2017;1504507. Doi: 10.1155/2017/1504507.
13. Oike H, Kobori M .Resveratrol regulates circa-dian clock genes in Rat-1 fibroblasts. Biosci Bio-technol Biochem, 72008; 2(11):3038-40. Doi: 10.1271/bbb.80426. Epub 2008.
14. Richards J,et al. Opposing actions of Per1 and Cry2 in the regulation of Per1 target gene ex-pression in the liver and kidney. Am J Physiol Regul Integr Comp Physiol, 2013; 305(7):R735-47. Doi: 10.1152/ajpregu.00195.2013. Epub 2013 Jul 3.; Bellfy, L., Smies, C.W., Bernhardt, A.R. et al. The clock gene Per1 may exert diurnal control over hippocampal memory consolidation. Neuropsychopharmacol. 2023; 48, 1789–1797. https://doi.org/10.1038/s41386-023-01616-1
15. Gao R, et al. Cryptochrome 1 activation inhibits melanogenesis and melanosome transport through negative regulation of cAMP/PKA/ CREB signaling pathway. Front Pharmacol, 2023; 6;14:1081030. Doi: 10.3389/fphar. 2023.1081030
16. Dierickx P, et al. SR9009 has REV-ERB-inde-pendent effects on cell proliferation and metab¬olism. Proc Natl Acad Sci U S A,2019;18;116 (25):12147-12152.
Doi: 10.1073/pnas.1904226116.
17. Raghavan PR. US Patents: 8,722,093 (2014); 9,034,383 (2015); 9,006,292; 2015.
18. Innovation Intelligence. https://www.else-vier.com/solutions/data-analytics.
19. Sivachenko, A. Y., Yuryev, A., Daraselia, N. & Mazo, I. Molecular networks in microarray anal¬ysis. J. Bioinform. Comput. Biol. 2007; 5, 429–456.
20. Nikitin, A., et al 2007. Pathway studio--the anal¬ysis and navigation of molecular networks. Bio¬informatics 2003; 19, 2155–2157.
21. .Tomczak, A. et al. Interpretation of biological experiments changes with evolution of the gene ontology and its annotations. Sci. Rep.20018; 8, 5115.
22. Zheng, Y. et al . Neural function of Bmal1: an overview. Cell Biosci 2023; 13, 1. https://doi.org/10.1186/s13578-022-00947-8
23. Cao X, et al Molecular mechanism of the repres¬sive phase of the mammalian circadian clock. Proc Natl Acad Sci USA, 12;118(2):e2021174118.
Doi: 10.1073/pnas.2021174118.
24. Marcheva B, et al. Circadian clocks and metab-olism. Handb Exp Pharmacol.2013; 217:127-55. Doi: 10.1007/978-3-642-25950-0_6. PMID: 23604478; PMCID: PMC4089089
25. Haque SN, et al. Effects of BMAL1 Manipulation on the Brain's Master Circadian Clock and Be¬havior. Yale J Biol Med. 2019; 27;92(2):251-258.
26. Takahashi JS . Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 2017; 18(3):164-179. Doi: 10.1038/nrg.2016. 150. Epub 2016 Dec 19
27. Trott AJ, Menet JS. Regulation of circadian clock transcriptional output by CLOCK: BMAL1. PLoS Genet 2018;14(1): e1007156. https://doi. org/10.1371/journal.pgen.1007156.
28. Cox KH, Takahashi JS. Circadian clock genes and the transcriptional architecture of the clock mechanism. J Mol Endocrinol. 2019; Nov;63(4): R93-R102. Doi: 10.1530/JME-19-0153.
29. Fagiani, F., Di Marino, D., Romagnoli, A. et al. Molecular regulations of circadian rhythm and implications for physiology and diseases. Sig Transduct Target Ther 2022; 7, 41. https://doi.org/10.1038/s41392-022-00899-y
30. Rijo-Ferreira, F., Takahashi, J.S. Genomics of cir¬cadian rhythms in health and disease. Genome Med, 2019; 11, 82 . https://doi.org/10.1186/s13073-019-0704-0.
31. Abe, Y.O. et al.Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals. Nat Commun,2022; 13, 4652. https://doi.org/10.1038/s41467-022-32326-9
32. Trott AJ, Menet JS. Regulation of circadian clock transcriptional output by CLOCK: BMAL1. PLoS Genet 2022; 14(1): e1007156. https://doi. org/10.1371/journal.pgen.1007156.
33. Han, et al. Role of Circadian Rhythm and Impact of Circadian Rhythm Disturbance on the Metab¬olism and Disease. Journal of Cardiovascular Pharmacology,2022; 79(3):p 254-263. Doi: 10.1097/FJC.0000000000001178.
34. Liu C, et al. Transcriptional coactivator PGC-1al¬pha integrates the mammalian clock and energy metabolism. Nature. 2007; 447(7143):477-81. Doi: 10.1038/nature05767).
35. Ray DW. Circadian Rhythm and Nuclear Recep¬tors, Adv Exp Med Biol, 2022; 1390:143-153. Doi: 10.1007/978-3-031-11836-4_8.
36. Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Re¬ceptors in Stem and Somatic Cells. Archives of Clinical and Biomedical Research.2023; 7: 524-536. DOI:10.26502/acbr.50170368.
37. Poliandri AH,et al. Modulation of clock gene ex¬pression by the transcriptional coregulator re¬ceptor interacting protein 140 (RIP140). J Biol Rhythms.2011; (3):187-99.
Doi: 10.1177/0748730411401579.
38. Crumbley C, Burris TP. Direct regulation of CLOCK expression by REV-ERB. PLoS One. 2011; 29;6(3):e17290. Doi: 10.1371/jour-nal.pone.0017290.
39. Qu M, et al . Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks. Proc Natl Acad Sci U S A, 2018; 115(52):E12305-E12312. Doi: 10.1073/pnas.1816411115.
40. Casey T, et al. Core circadian clock transcription factor BMAL1 regulates mammary epithelial cell growth, differentiation, and milk component syn¬thesis. PLoS One, 2021; 6(8):e0248199.
41. Yang X. A wheel of time. The circadian clock, nu¬clear receptors, and physiology. Genes Dev 2010; 15;24(8):741-7. Doi: 10.1101/gad. 1920710.
42. Akashi M, Takumi T. The orphan nuclear receptor ROR alpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol. 2—5; 12(5):441-8.
Doi: 10.1038/nsmb925.
43. Liang H, Ward WF. PGC-1alpha: a key regula¬tor of energy metabolism. Adv Physiol Educ. 2006; Dec;30(4):145-51. Doi: 10.1152/ad¬van.00052.2006.
44. Raghavan.P.R Metadichol a Sirtuin Modulator for Anti-Aging Therapies This is a preprint;. .https://doi.org/10.21203/rs.3.rs-3199226/v2.
45. Masri S, Sassone-Corsi P. Sirtuins and the circa-dian clock: bridging chromatin and metabolism. Sci Signal,2014; 7(342):re6.
Doi: 10.1126/scisignal.2005685.
46. Sun S, et al 2019. Sirt6 deacetylase activity regulates circadian rhythms via Per2. Biochem Biophys Res Commun, 2019; 511(2):234-238. Doi: 10.1016/j.bbrc.2019.01.143.
47. Becherini, P., Caffa, I., Piacente, F. et al. SIRT6 enhances oxidative phosphorylation in breast cancer and promotes mammary tumorigenesis in mice. Cancer Metab, 2021; 9, 6. https://doi.org/10.1186/s40170-021-00240-1.
48. Desantis V, Lamanuzzi A, Vacca A. The role of SIRT6 in tumors. Hematologica. 2018; Jan;103(1):1-4.
Doi: 10.3324/hema¬tol.2017.182675.
49. Raghu S, Prabhashankar AB, Shivanaiah B, Tripathi E, Sundaresan NR. Sirtuin 6 Is a Critical Epigenetic Regulator of Cancer. Subcell Bio-chem. 2022;100:337-360. Doi: 10.1007/978-3-031-07634-3_10.
50. Soni, S.K., Basu, P., Singaravel, M. et al. Sirtuins and the circadian clock interplay in cardiopro-tection: focus on sirtuin 1. Cell. Mol. Life Sci.2021;78, 2503–2515. https://doi.org/10.1007/s00018-020-03713-6
51. Bellet MM, et al. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. Proc Natl Acad Sci U S A, 2013; 110(9):3333-8.
Doi: 10.1073/pnas.1214266110
52. Zhou S, et al. Circadian Clock and Sirtuins in Di¬abetic Lung: A Mechanistic Perspective. Front En¬docrinol (Lausanne),2020;1:173. Doi: 10.3389/ fendo.2020.00173.
53. Jung-Hynes et al. J Pineal Res, 2010; 48(1):9-19. Doi: 10.1111/j.1600-079X.2009.00729.x.
54. Ribeiro, R.F.N et al 2022. . SIRT1 activation and its circadian clock control: a promising approach against frailty in neurodegenerative disorders. Aging Clin Exp Res, 2016; 34, 2963–2976 . https://doi.org/10.1007/s40520-022-02257-y.
55. Wang, RH et al.Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging. Sci Rep,2016; 6, 28633. https://doi.org/10.1038/srep28633.
56. Chandramowlishwaran P. Role of Sirtuins in Modulating Neurodegeneration of the Enteric Nervous System and Central Nervous System. Front Neurosci. 2020;14:614331. Doi: 10.3389/fnins.2020.614331.
57. Chang HC, Guarente L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell, 2013; 153(7):1448-60. Doi: 10.1016/j.cell.2013.05.027.
58. Masri S . Sirtuin-dependent clock control: new advances in metabolism, aging and cancer. Curr Opin Clin Nutr Metab Care. 2015; 18(6):521-7. Doi: 10.1097/MCO.0000000000000219.
59. Fagiani, F. et al. Molecular regulations of circa-dian rhythm and implications for physiology and diseases. Sig Transduct Target The,2022; r 7, 4. https://doi.org/10.1038/s41392-022-00899-y
60. Soni, S.K., et al. Sirtuins and the circadian clock interplay in cardioprotection: focus on sirtuin 1. Cell. Mol. Life Sci. 2021; 78, 2503–2515. https://doi.org/10.1007/s00018-020-03713-6
61. Bellet MM, et al. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. Proc Natl Acad Sci U S A, 2013; 26;110(9):3333-8.
Doi: 10.1073/pnas.1214266110
62. Zhou S, et al. Circadian Clock and Sirtuins in Di¬abetic Lung: A Mechanistic Perspective. Front En¬docrinol (Lausanne), 2020; 3;11:173. Doi: 10.3389/fendo.2020.00173.
63. Jung-Hynes B, et al. Sirtuins, melatonin and cir-cadian rhythms: building a bridge between ag-ing and cancer. J Pineal Res. 2010; 48(1):9-19. Doi: 10.1111/j.1600-079X.2009.00729.x.
64. P R. Raghavan, "Metadichol®: A Novel Nano-lipid Formulation That Inhibits SARS-CoV-2 and a Multitude of Pathological Viruses In Vitro", Bi-oMed Research International, 2022; vol.2022, Article ID 1558860, 14 pages. https://doi.org/10.1155/2022/1558860
65. P.R. Raghavan. Metadichol is a natural ligand for expressing Yamanaka reprogramming fac-tors in somatic and primary cancer cell lines Pre¬print 2023; https://doi.org/10.21203/rs.3.rs-1727437/v4.
66. C. Aleman, et al. A 12-month study of policosa-nol oral toxicity in Sprague Dawley rats,” Toxi-cology Letters, 1994; vol. 70, no. 1, pp. 77–87.
67. C. L. Alemán, et al. Carcinogenicity of policosa-nol in Sprague Dawley rats: a 24-month study, Teratogenesis, Carcinogenesis, and Mutagene-sis, 1994; vol. 14, no. 5, pp. 239–249,.
68. C. L. Alemán, et al. Carcinogenicity of policosa-nol in mice: an 18-month study,” Food and Chem¬ical Toxicology, 1995; vol. 33, no. 7, pp. 573–578.
2. Physiology; Circadian rhythms. https://www.ncbi.nlm.nih.gov/books/NBK519507/
3. Rijo-Ferreira, F., Takahashi, J.S. Genomics of cir¬cadian rhythms in health and disease. Genome Med, 2019; 11, 82 https://doi.org/10.1186/s13073-019-0704-0.
4. Trott AJ, Menet JS. Regulation of circadian clock transcriptional output by CLOCK:BMAL1. PLoS Genet. 2018; Jan 4;14(1):e1007156. Doi: 10.1371/journal.pgen.1007156.
5. Alex A Koch ,et al. 2022. Quantification of pro¬tein abundance and interaction defines a mech¬anism for operation of the circadian clock eLife 11:e73976. https://doi.org/10.7554/eLife.73976.
6. Kawai M, Rosen CJ. PPARγ: a circadian tran-scription factor in adipogenesis and osteogene-sis. Nat Rev Endocrinol. 2010 ;Nov;6(11):629-36. Doi: 10.1038/nrendo.2010.155.
7. Liu H, Liu Y, Hai R, Liao W, Luo X. The role of circadian clocks in cancer: Mechanisms and clini¬cal implications. Genes Dis. 2022; May 28;10 (4):1279-1290. Doi: 10.1016/j.gen-dis.2022. 05.014.
8. Zhang W, Xiong Y, Tao R, Panayi AC, Mi B, Liu G. Emerging Insight into the Role of Circadian Clock Gene BMAL1 in Cellular Senescence. Front Endocrinol (Lausanne). 2022; Jun 6;13:915139. Doi: 10.3389/fendo.2022.915139.
9. Yanling Xie Front. Physiol., 2019; New Insights into the Circadian Rhythm and Its Related Dis-eases Sec. Chronobiology Volume 10. | https://doi.org/10.3389/fphys.2019.00682.
10. Walker, W.H., Walton, J.C., DeVries, A.C. et al. Circadian rhythm disruption and mental health. Transl Psychiatry, 2020; 10, 28. https://doi.org/10.1038/s41398-020-0694-0.
11. A Zhang W, Xiong Y, Tao R, Panayi AC, Mi B, Liu G. Emerging Insight into the Role of Circadian Clock Gene BMAL1 in Cellular Senescence. Front Endocrinol (Lausanne). 2022; Jun 6;13:915139. Doi: 10.3389/fendo.2022.915139.
12. Vadnie CA, McClung CA. Circadian Rhythm Dis-turbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus. Neural Plast. 2017;1504507. Doi: 10.1155/2017/1504507.
13. Oike H, Kobori M .Resveratrol regulates circa-dian clock genes in Rat-1 fibroblasts. Biosci Bio-technol Biochem, 72008; 2(11):3038-40. Doi: 10.1271/bbb.80426. Epub 2008.
14. Richards J,et al. Opposing actions of Per1 and Cry2 in the regulation of Per1 target gene ex-pression in the liver and kidney. Am J Physiol Regul Integr Comp Physiol, 2013; 305(7):R735-47. Doi: 10.1152/ajpregu.00195.2013. Epub 2013 Jul 3.; Bellfy, L., Smies, C.W., Bernhardt, A.R. et al. The clock gene Per1 may exert diurnal control over hippocampal memory consolidation. Neuropsychopharmacol. 2023; 48, 1789–1797. https://doi.org/10.1038/s41386-023-01616-1
15. Gao R, et al. Cryptochrome 1 activation inhibits melanogenesis and melanosome transport through negative regulation of cAMP/PKA/ CREB signaling pathway. Front Pharmacol, 2023; 6;14:1081030. Doi: 10.3389/fphar. 2023.1081030
16. Dierickx P, et al. SR9009 has REV-ERB-inde-pendent effects on cell proliferation and metab¬olism. Proc Natl Acad Sci U S A,2019;18;116 (25):12147-12152.
Doi: 10.1073/pnas.1904226116.
17. Raghavan PR. US Patents: 8,722,093 (2014); 9,034,383 (2015); 9,006,292; 2015.
18. Innovation Intelligence. https://www.else-vier.com/solutions/data-analytics.
19. Sivachenko, A. Y., Yuryev, A., Daraselia, N. & Mazo, I. Molecular networks in microarray anal¬ysis. J. Bioinform. Comput. Biol. 2007; 5, 429–456.
20. Nikitin, A., et al 2007. Pathway studio--the anal¬ysis and navigation of molecular networks. Bio¬informatics 2003; 19, 2155–2157.
21. .Tomczak, A. et al. Interpretation of biological experiments changes with evolution of the gene ontology and its annotations. Sci. Rep.20018; 8, 5115.
22. Zheng, Y. et al . Neural function of Bmal1: an overview. Cell Biosci 2023; 13, 1. https://doi.org/10.1186/s13578-022-00947-8
23. Cao X, et al Molecular mechanism of the repres¬sive phase of the mammalian circadian clock. Proc Natl Acad Sci USA, 12;118(2):e2021174118.
Doi: 10.1073/pnas.2021174118.
24. Marcheva B, et al. Circadian clocks and metab-olism. Handb Exp Pharmacol.2013; 217:127-55. Doi: 10.1007/978-3-642-25950-0_6. PMID: 23604478; PMCID: PMC4089089
25. Haque SN, et al. Effects of BMAL1 Manipulation on the Brain's Master Circadian Clock and Be¬havior. Yale J Biol Med. 2019; 27;92(2):251-258.
26. Takahashi JS . Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 2017; 18(3):164-179. Doi: 10.1038/nrg.2016. 150. Epub 2016 Dec 19
27. Trott AJ, Menet JS. Regulation of circadian clock transcriptional output by CLOCK: BMAL1. PLoS Genet 2018;14(1): e1007156. https://doi. org/10.1371/journal.pgen.1007156.
28. Cox KH, Takahashi JS. Circadian clock genes and the transcriptional architecture of the clock mechanism. J Mol Endocrinol. 2019; Nov;63(4): R93-R102. Doi: 10.1530/JME-19-0153.
29. Fagiani, F., Di Marino, D., Romagnoli, A. et al. Molecular regulations of circadian rhythm and implications for physiology and diseases. Sig Transduct Target Ther 2022; 7, 41. https://doi.org/10.1038/s41392-022-00899-y
30. Rijo-Ferreira, F., Takahashi, J.S. Genomics of cir¬cadian rhythms in health and disease. Genome Med, 2019; 11, 82 . https://doi.org/10.1186/s13073-019-0704-0.
31. Abe, Y.O. et al.Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals. Nat Commun,2022; 13, 4652. https://doi.org/10.1038/s41467-022-32326-9
32. Trott AJ, Menet JS. Regulation of circadian clock transcriptional output by CLOCK: BMAL1. PLoS Genet 2022; 14(1): e1007156. https://doi. org/10.1371/journal.pgen.1007156.
33. Han, et al. Role of Circadian Rhythm and Impact of Circadian Rhythm Disturbance on the Metab¬olism and Disease. Journal of Cardiovascular Pharmacology,2022; 79(3):p 254-263. Doi: 10.1097/FJC.0000000000001178.
34. Liu C, et al. Transcriptional coactivator PGC-1al¬pha integrates the mammalian clock and energy metabolism. Nature. 2007; 447(7143):477-81. Doi: 10.1038/nature05767).
35. Ray DW. Circadian Rhythm and Nuclear Recep¬tors, Adv Exp Med Biol, 2022; 1390:143-153. Doi: 10.1007/978-3-031-11836-4_8.
36. Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Re¬ceptors in Stem and Somatic Cells. Archives of Clinical and Biomedical Research.2023; 7: 524-536. DOI:10.26502/acbr.50170368.
37. Poliandri AH,et al. Modulation of clock gene ex¬pression by the transcriptional coregulator re¬ceptor interacting protein 140 (RIP140). J Biol Rhythms.2011; (3):187-99.
Doi: 10.1177/0748730411401579.
38. Crumbley C, Burris TP. Direct regulation of CLOCK expression by REV-ERB. PLoS One. 2011; 29;6(3):e17290. Doi: 10.1371/jour-nal.pone.0017290.
39. Qu M, et al . Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks. Proc Natl Acad Sci U S A, 2018; 115(52):E12305-E12312. Doi: 10.1073/pnas.1816411115.
40. Casey T, et al. Core circadian clock transcription factor BMAL1 regulates mammary epithelial cell growth, differentiation, and milk component syn¬thesis. PLoS One, 2021; 6(8):e0248199.
41. Yang X. A wheel of time. The circadian clock, nu¬clear receptors, and physiology. Genes Dev 2010; 15;24(8):741-7. Doi: 10.1101/gad. 1920710.
42. Akashi M, Takumi T. The orphan nuclear receptor ROR alpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol. 2—5; 12(5):441-8.
Doi: 10.1038/nsmb925.
43. Liang H, Ward WF. PGC-1alpha: a key regula¬tor of energy metabolism. Adv Physiol Educ. 2006; Dec;30(4):145-51. Doi: 10.1152/ad¬van.00052.2006.
44. Raghavan.P.R Metadichol a Sirtuin Modulator for Anti-Aging Therapies This is a preprint;. .https://doi.org/10.21203/rs.3.rs-3199226/v2.
45. Masri S, Sassone-Corsi P. Sirtuins and the circa-dian clock: bridging chromatin and metabolism. Sci Signal,2014; 7(342):re6.
Doi: 10.1126/scisignal.2005685.
46. Sun S, et al 2019. Sirt6 deacetylase activity regulates circadian rhythms via Per2. Biochem Biophys Res Commun, 2019; 511(2):234-238. Doi: 10.1016/j.bbrc.2019.01.143.
47. Becherini, P., Caffa, I., Piacente, F. et al. SIRT6 enhances oxidative phosphorylation in breast cancer and promotes mammary tumorigenesis in mice. Cancer Metab, 2021; 9, 6. https://doi.org/10.1186/s40170-021-00240-1.
48. Desantis V, Lamanuzzi A, Vacca A. The role of SIRT6 in tumors. Hematologica. 2018; Jan;103(1):1-4.
Doi: 10.3324/hema¬tol.2017.182675.
49. Raghu S, Prabhashankar AB, Shivanaiah B, Tripathi E, Sundaresan NR. Sirtuin 6 Is a Critical Epigenetic Regulator of Cancer. Subcell Bio-chem. 2022;100:337-360. Doi: 10.1007/978-3-031-07634-3_10.
50. Soni, S.K., Basu, P., Singaravel, M. et al. Sirtuins and the circadian clock interplay in cardiopro-tection: focus on sirtuin 1. Cell. Mol. Life Sci.2021;78, 2503–2515. https://doi.org/10.1007/s00018-020-03713-6
51. Bellet MM, et al. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. Proc Natl Acad Sci U S A, 2013; 110(9):3333-8.
Doi: 10.1073/pnas.1214266110
52. Zhou S, et al. Circadian Clock and Sirtuins in Di¬abetic Lung: A Mechanistic Perspective. Front En¬docrinol (Lausanne),2020;1:173. Doi: 10.3389/ fendo.2020.00173.
53. Jung-Hynes et al. J Pineal Res, 2010; 48(1):9-19. Doi: 10.1111/j.1600-079X.2009.00729.x.
54. Ribeiro, R.F.N et al 2022. . SIRT1 activation and its circadian clock control: a promising approach against frailty in neurodegenerative disorders. Aging Clin Exp Res, 2016; 34, 2963–2976 . https://doi.org/10.1007/s40520-022-02257-y.
55. Wang, RH et al.Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging. Sci Rep,2016; 6, 28633. https://doi.org/10.1038/srep28633.
56. Chandramowlishwaran P. Role of Sirtuins in Modulating Neurodegeneration of the Enteric Nervous System and Central Nervous System. Front Neurosci. 2020;14:614331. Doi: 10.3389/fnins.2020.614331.
57. Chang HC, Guarente L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell, 2013; 153(7):1448-60. Doi: 10.1016/j.cell.2013.05.027.
58. Masri S . Sirtuin-dependent clock control: new advances in metabolism, aging and cancer. Curr Opin Clin Nutr Metab Care. 2015; 18(6):521-7. Doi: 10.1097/MCO.0000000000000219.
59. Fagiani, F. et al. Molecular regulations of circa-dian rhythm and implications for physiology and diseases. Sig Transduct Target The,2022; r 7, 4. https://doi.org/10.1038/s41392-022-00899-y
60. Soni, S.K., et al. Sirtuins and the circadian clock interplay in cardioprotection: focus on sirtuin 1. Cell. Mol. Life Sci. 2021; 78, 2503–2515. https://doi.org/10.1007/s00018-020-03713-6
61. Bellet MM, et al. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. Proc Natl Acad Sci U S A, 2013; 26;110(9):3333-8.
Doi: 10.1073/pnas.1214266110
62. Zhou S, et al. Circadian Clock and Sirtuins in Di¬abetic Lung: A Mechanistic Perspective. Front En¬docrinol (Lausanne), 2020; 3;11:173. Doi: 10.3389/fendo.2020.00173.
63. Jung-Hynes B, et al. Sirtuins, melatonin and cir-cadian rhythms: building a bridge between ag-ing and cancer. J Pineal Res. 2010; 48(1):9-19. Doi: 10.1111/j.1600-079X.2009.00729.x.
64. P R. Raghavan, "Metadichol®: A Novel Nano-lipid Formulation That Inhibits SARS-CoV-2 and a Multitude of Pathological Viruses In Vitro", Bi-oMed Research International, 2022; vol.2022, Article ID 1558860, 14 pages. https://doi.org/10.1155/2022/1558860
65. P.R. Raghavan. Metadichol is a natural ligand for expressing Yamanaka reprogramming fac-tors in somatic and primary cancer cell lines Pre¬print 2023; https://doi.org/10.21203/rs.3.rs-1727437/v4.
66. C. Aleman, et al. A 12-month study of policosa-nol oral toxicity in Sprague Dawley rats,” Toxi-cology Letters, 1994; vol. 70, no. 1, pp. 77–87.
67. C. L. Alemán, et al. Carcinogenicity of policosa-nol in Sprague Dawley rats: a 24-month study, Teratogenesis, Carcinogenesis, and Mutagene-sis, 1994; vol. 14, no. 5, pp. 239–249,.
68. C. L. Alemán, et al. Carcinogenicity of policosa-nol in mice: an 18-month study,” Food and Chem¬ical Toxicology, 1995; vol. 33, no. 7, pp. 573–578.