Introduction: What they say:
A recent study from Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA; Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China; and Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA shows that “Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration.” This study was published, in the 16 Feb 2018 issue of Nature communications (one of the best journals in science with an impact factor of 16+), by Prof Wang Y, Huang W, and others.
What we say:
On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Senolytics therapy for cardiac repair, cardiac regeneration and cardioprotection: Combinatorial therapy for postnatal Cardiomyocyte proliferation, repair and regeneration: A two-component Pill consisting of Dasatinib and Quercetin (Pill-DQ) decreases tumor suppressor MiR-128 and cyclin-dependent kinase inhibitor p27 expression, increases SUZ12 expression, increases Cyclin E and CDK2 expression, promotes proliferation/re-entry of postnatal/adult cardiomyocytes, attenuates fibrosis, ameliorates cardiac dysfunction, and promotes heart repair in response to myocardial infarction, via up-regulation of its target gene
From the significance of the study to public health relevance:
Given that: (1) cardiovascular disease is the leading cause of death worldwide; (2) the raise of death rate, due to cardiovascular disease, has increased from 123 lakhs in 1990 to 173 lakhs in 2013; (3) 85% of people over 80 years are susceptible to cardiovascular diseases;(4) in India, in 2004, 14.6 lakhs deaths (14% of total deaths) were due to ischemic heart disease; (5) the death due to cardiovascular disease is higher in low-to-middle income countries compared to developed countries; (6) the global economic cost spent in the treatment of cardiovascular disease in 2011 was little more than 10 billion US dollars; (7) an alarming number of people, such as 230 lakhs people, will die from cardiovascular diseases each year by 2030, there is an urgent need to find: (i) a way to induce regeneration of cardiomyocytes that were lost in Myocardial patients; (ii) a cheaper alternative to the existing expensive drugs; and (iii) a side-effect-free Natural product-based drug.
What is known?
Prof Wang’s research team has shown recently that: (1) miRNA-128 is upregulated in terminally differentiated cardiomyocytes (CMs); (2) Overexpression of MiR-128 in cardiomyocytes inhibits cardiomyocyte proliferation and function; (3) Deletion of miR-128 in postnatal cardiomyocytes increase proliferation by increasing the expression of DNA modifying protein SUZ12; (4) Increased expression of Suz12 inhibits the expression of cyclin-dependent kinase inhibitor p27; (5) Down-regulation of p27 results in increased expression of the positive regulators of cell cycle, such as Cyclin E and CDK2; and (6) Deletion of MiR-128: (a) drives adult cardiomyocytes to re-enter into cell cycle; (b) attenuates fibrosis; and (c) suppresses cardiac dysfunction in response to myocardial infarction, suggesting that inhibition of miR-128 expression may promote cardiomyocyte proliferation and heart regeneration.
From research findings to therapeutic opportunity:
A study from the School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Kings College London, London, UK, Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, Minnesota, School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, Kings College London, London, UK, National Heart and Lung Institute, Imperial College London, London, UK.5 Barts Health NHS Trust, London, UK. and Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy shows that “Aged-senescent cells contribute to impaired heart regeneration.” This study was published, in the 10 March 2019 issue of of the prestigious journal Ageing cell (Impact factor: +7.627), by Prof. Georgina May Ellison-Hughes, Ph.D., and others.
It is known for years that ageing augments cellular senescence and decreases the regenerative capability of tissue-specific stem/progenitor cells.
This study shows/suggests that: (1) cardiac progenitor cells (CPCs) isolated from patients, aged 32-86 years, are senescent and poorly replicate, regenerate and differentiate; (2) Senescence-Associated Secretory Phenotype (SASP) factors secreted by senescent CPCs promote healthy cells to undergo senescence; and (3) Removal or elimination of senescent cells using a senolytic cocktail consisting of Dasatinib and Quercetin (DQ) activates CPCs, suggesting that agents that eliminate or remove senescent cells will promote the regenerative capacity of the heart. However, the precise mechanism of action DQ remains unclear.
The study presented here substantiates and supports the aforementioned study’s’ claim, and of others, by providing detailed mechanistic insights into how a pill consisting of Dasatinib and Quercetin (DQ) attenuates and protects against myocardial dysfunction, including cardiac hypertrophy, fibrosis of the myocardium, cardiac ageing and myocardial infarction.
Pill-DQ [Dasatinib and Quercetin (DQ)], by increasing the expression of its target genes, it may decrease the expression of tumor suppressor gene miRNA-128 (that impedes postnatal cardiomyocyte proliferation) (fig.1). Thereby, it could: (1) increase the expression of Suz12;(2) decrease the expression of CDK inhibitor p27; (3) increase the expression of gene products that promote cardiac proliferation, including Cyclin E and CDK2;(4) increase the expression of miRNAs that promote cardiac regeneration;(5) increase post-natal cardiomyocyte proliferation; (6) suppress fibrosis; (7) promote cardiomyocyte survival/regeneration; (8) promote cardiomyocyte repair, and recovery after myocardial infarction; (9) attenuate cardiac ageing; and (10) extend lifespan (fig 1). Thus, by treating cardiac patients with Pill-DQ or its analogs or equivalents that share their mechanism of action, one may preserve myocardial function after myocardial infarction; and prevent aging-associated (or, stress-associated) decline in cardiac function.
In conclusion, this study suggests, for the first time, with detailed mechanistic insights, that pharmacological formulations encompassing “a two-component pill consisting of Dasatinib and Quercetin (DQ) or its analogs or functional equivalents that share their mechanism of action, either alone or in combination with any of the known compounds that improve myocardial function,” may be used to heal damaged cardiac tissue, and repair and regenerate new cardiomyocytes after myocardial infarction (fig.2).
Together, the study presented here, provides, for the first time, plausible explanation and mechanistic and functional insights into how pill-DQ may attenuate the risk of cardiac dysfunction.
Thus, those who are above 55 years of age, by taking pill-DQ, they may prevent ageing-associated (or, stress-associated) decline in cardiac function and cardiac dysfunction (fig. 2).
Finally, this study provides, for the first time, mechanistic and functional insights into how pill-DQ may protect against cardiac dysfunction and heart failure in the long-term (figs. 4-5).
Details of the research findings:
Idea Proposed/Formulated (with experimental evidence) by:
Dr L Boominathan Ph.D.
Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/
Undisclosed mechanistic information: How does Pill-DQ decrease the expression of MiR-128 and p27 and promote postnatal cardiomyocyte proliferation, repair and regeneration?
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References: Polypill can protect against cardiac dysfunction.
Web:http://genomediscovery.org or http://newbioideas.com/
Citation: Boominathan, L. Senolytics therapy for cardiac repair, cardiac regeneration and cardioprotection: Combinatorial therapy for postnatal Cardiomyocyte proliferation, repair and regeneration: A two-component Pill consisting of Dasatinib and Quercetin (Pill-DQ) decreases tumor suppressor MiR-128 and cyclin-dependent kinase inhibitor p27 expression, increases SUZ12 expression, increases Cyclin E and CDK2 expression, promotes proliferation/re-entry of postnatal/adult cardiomyocytes, attenuates fibrosis, ameliorates cardiac dysfunction, and promotes heart repair in response to myocardial infarction, via up-regulation of its target gene, 20/September/2019, 7.39 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org
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