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Combinatorial therapy for cardiomyocyte proliferation and heart regeneration: A pharmaceutical mixture encompassing L-Malate, Lithium and Imidazopyridine derivative (X22) (MLX22) 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, 1/June/2018, 10.51 pm

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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 12+), 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:  Combinatorial therapy for cardiomyocyte proliferation and heart regeneration: A pharmaceutical mixture encompassing L-Malate, Lithium and Imidazopyridine derivative (X22) (MLX22decreases 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 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; (3) the death due to cardiovascular disease is higher in low-to-middle income countries compared to developed countries; (4) the global economic cost spent in the treatment of cardiovascular disease in 2011 was little more than 10 billion US dollars; (5) 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 (iv) 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 modyfing protein SUZ12; (4) Increased expression of Suz12 inhibits the expression of cyclin-dependent kinase inhibitor p27; (5) Down regulation of p27 results in incresed 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 reenter 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:

This study suggests a combinatorial therapy for heart regeneration and repair. A pharmaceutical mixture encompassing L-Malate, Lithium and Imidazopyridine derivative (X22) (MLX22), by increasing the expression of their target genes, they may decrease the expression of MiRNA-128 (fig.1). Thereby, they may: (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 cardiomyocyte proliferation; (6) suppress fibrosis; (7) promote cardiomyocyte survival/regeneration; (8) promote recovery after myocardial infarction; and (9) extend life span (fig 1). Thus, by treating cardiac patients with CMG, one may preserve myocardial function after myocardial infarction and prevent ageing-associated (or, stress-associated) decline in cardiac function. Together, this study suggests that pharmacological formulations encompassing L-Malate, Lithium and Imidazopyridine derivative (X22) (MLX22or their analogs, either alone or in combination with any of the known compounds that improve myocardial function,” may be used to heal damaged cardiac tissue and regenerate new cardiomyocytes after myocardial infarction (fig.2).

Figure 1. Agavins function as Cardioprotective agents. Mechanistic insights into how Agavin decreases the expression of MiR-128, and CDKI p27,  increases the expression of Cyclin E and CDK2, and regulates  the expression of other genes that promote cardiac repair and regeneration.

Figure 2. The chemical structure of Agavins. Agavin, isolated from Agavi, may function as a cardioprotective agent through induction of  MiR-128, CDKI p27 and down regulation of Cyclin E and CDK2

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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  a pharmaceutical mixture encompassing L-Malate, Lithium and Imidazopyridine derivative (X22) (MLX22decrease the expression of MiR-128 and p27 and promote cardiac proliferation, regeneration and repair

Amount: $ 500 #

# Research cooperation

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References:

Web:http://genomediscovery.org or http://newbioideas.com/

Citation: Boominathan, L., Combinatorial therapy for cardiomyocyte proliferation and heart regeneration: A pharmaceutical mixture encompassing L-Malate, Lithium and Imidazopyridine derivative (X22) (MLX22decreases 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, 1/June/2018, 10.51 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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