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Treatment for Age-related Macular Degeneration
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Jamila Aug 04, 2020
What methods can be used to control in vivo cellular reprogramming?
Image credit: Ocampo et al. 2016 (https://www.sciencedirect.com/science/article/pii/S0092867416316646)
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What methods can be used to control in vivo cellular reprogramming?
The Yamanaka factors (OKSM) were the first factors to be used to create induced pluripotent stem cells (iPSC) from somatic cells in a process called cellular reprogramming. Recently, various combinations of small molecules have also been able to conduct cellular reprogramming.
Ocampo and colleagues used partial cellular reprogramming to reverse the hallmarks of aging and to extend the lifespan of mice. The researchers used partial reprogramming because prolonged cellular reprogramming in vivo resulted in the development of teratomas and loss of somatic identity which led to death. Therefore, it is vital that cellular reprogramming can be controlled.
Previous studies have used doxycycline (dox) to control in vivo cellular reprogramming, doxycycline-inducible systems are reversible but doxycycline may be toxic when used at low concentrations for a prolonged period. Therefore, more drug-inducible systems should be developed for cellular reprogramming.
[1]Ma, Xiaojie, Linghao Kong, and Saiyong Zhu. "Reprogramming cell fates by small molecules." Protein & cell 8.5 (2017): 328-348.
[2]Ocampo, Alejandro, et al. "In vivo amelioration of age-associated hallmarks by partial reprogramming." Cell 167.7 (2016): 1719-1733.
[3]Tamanini, S., G. P. Comi, and S. Corti. "In vivo transient and partial cell reprogramming to pluripotency as a therapeutic tool for neurodegenerative diseases." Molecular neurobiology 55.8 (2018): 6850-6862.
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Creative contributions
Use of artificial transcription factors
Artificial transcription factors have an edge over the natural ones when utilized for reprogramming. Identifying natural transcription factors of interest is challenging. We need prior knowledge of their expression profiles and function during differentiation to a desired cell type. [1] Furthermore, identification of transcription factors expressed in the desired cell type may only reflect those that are necessary to maintain that cell state, not those that were temporarily expressed to reach that state. [2] Also, expressing the correct combinations and levels of transcription factors required to achieve desired cell fate involves a trial-and-error method of screening that is often prone to failure and requires substantial time, labor, and financial resources. And natural transcription factors are subject to feedback regulation, dependence on partner proteins that may not be expressed in the starting cell type, epigenetic barriers that prevent binding to target sites in the genome, and other processes that prevent departure from a given homeostatic state.
Such challenges can be overcome by use of artificial transcription factors that directly target key gene regulatory networks of interest. Multiple artificial transcription factors can be used to alter the expression of multiple gene targets at the same time. [3]
1. Zhang H-M, Chen H, Liu W, Liu H, Gong J, Wang H, et al. AnimalTFDB: a comprehensive animal transcription factor database. Nucleic Acids Res [Internet]. 2012 Jan 1;40(D1):D144–9. Available from: https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkr965
2. Rosenfeld MG. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev [Internet]. 2006 Jun 1;20(11):1405–28. Available from: http://www.genesdev.org/cgi/doi/10.1101/gad.1424806
3. Pandelakis M, Delgado E, Ebrahimkhani MR. CRISPR-Based Synthetic Transcription Factors In Vivo: The Future of Therapeutic Cellular Programming. Cell Syst [Internet]. 2020 Jan;10(1):1–14. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2405471219303485
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Regenerative Medicine: somatic cell reprogramming with drugs cocktail .
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The pharmacological manipulation of tissues uses innate mechanisms of the cell in order to regulate molecular processes such as DNA transcription, to subsequently achieve a specific cellular phenotype. Through different chemical modifications, such as the use of histone methylation inhibitors, DNA methyltransferase inhibitors, among others, they can help to remodel the structure and balance of chromatin. The processes by which chromatin states are modified (thanks to the modulation of enzymatic activity) are DNA methylation, histone methylation and acetylation, to name the main ones. Pharmacological agents can also modulate gene expression through cell signaling pathways, such as specific small molecule inhibitors, by inhibiting surface proteins and second messengers. Signaling proteins, such as growth factors, can interact with receptor proteins on the cell surface to trigger intracellular signaling cascades. It is a transduction of external signals in the cell to modulate gene expression. Using this principle of modulating cellular activity through the use of drug components, Min Xie and colleagues create known drug cocktails to achieve the desired cell reprogramming. Once a new chemical candidate is found, it is added to an individual cocktail and the improvement of the reprogramming process is evaluated. Once these beneficial agents have been identified, they are incorporated into the pharmacological cocktail in order to achieve a synergistic effect between the different agents. [1] The resulting cocktail can be interactively optimized to achieve the desired result of cell reprogramming. It would be interesting to start thinking about how the performance of this process of selection of cell reprogramming agents can be improved, to make this process more dynamic and efficient.
References
Xie M, Tang S, Li K, Ding S. Pharmacological Reprogramming of Somatic Cells for Regenerative Medicine. Acc Chem Res. 2017; 50 (5): 1202-1211. doi: 10.1021 / acs.accounts.7b00020
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Jamila 4 years ago
In a previous study, bioinformatics and deep learning methods were applied to the datasets available on the LINCS website (http://www.lincsproject.org/). This helped to determine the gene(s) and pathway(s) patterns involved in drugs like metformin and rapamycin. The researchers were able to screen drug matches with hundreds of compounds using this method. (https://pubmed.ncbi.nlm.nih.gov/29165314/) Perhaps this method could be used to identify reprogramming agents similar to the ones we already know about.
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Calcium: age-related bioelement in thrombosis process.
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Calcium is intimately related to the thrombosis process since it participates in the coagulation cascade, atherosclerosis processes, cardiovascular diseases (CVD), among other nosological entities related to aging. It is an ion present at multiple cellular processes, such as muscle contraction, nerve impulse, apoptosis, and regulation of the hemostasis cascade, among many others. When the cell is stimulated, calcium enters the cell from extracellular compartments to activate proteins that carry out corresponding actions. Intracellular calcium is typically 10,000 to 100,000 times lower than the extracellular level. This molecule is the most abundant mineral in the human body with an approximate amount of 1.5 kg, most of which resides in teeth and bones [1]. Older people have decreased bone mineral density, which is why doctors and nutritionists often recommend the intake of supplements with calcium. For people over 65, a daily calcium intake of more than 1500 mg is recommended. Different studies have inconclusive results if indeed the consumption of calcium supplements has an effect on the development of cardiovascular diseases. From five prospective studies that have specifically examined the use of calcium as a supplement and the risk of CVD, four studies found no significant associations. In a cohort study of 2,183 middle-aged Swedish men, the occurrence of thrombotic events was independent from blood calcium concentration. Consistent with this, a Finnish cohort study did not associate calcaemia with the development of strokes and myocardial infarctions either. [2] Because of what has been stated so far, it is necessary to standardize and make a properly updated classification relating the concentration of calcium in the blood and presence of comorbidities with the concentration of supplementary calcium to be applied in these patients, in order to minimize the risk of appearance or exacerbation of CVD. It is necessary to have more data recollection for a concrete and useful analysis.
References
Vaskonen T. Dietary minerals and modification of cardiovascular risk factors. J Nutr Biochem. 2003; 14 (9): 492-506.
doi: 10.1016 / s0955-2863 (03) 00074-3
Wang L, Manson JE, Sesso HD. Calcium intake and risk of cardiovascular disease: a review of prospective studies and randomized clinical trials. Am J Cardiovasc Drugs. 2012; 12 (2): 105-116. doi: 10.2165 / 11595400-000000000-00000
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