Investigating the role of Sirtuins in cell reprogramming

NAD+ was discovered during yeast fermentation, and since its discovery, its important roles in redox metabolism, aging, and longevity, the immune system and DNA repair have been highlighted. A deregulation of the NAD+ levels has been associated with metabolic diseases and aging-related diseases, including neurodegeneration, defective immune responses, and cancer. NAD+ acts as a cofactor through its interplay with NADH, playing an essential role in many enzymatic reactions of energy metabolism, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle. NAD+ also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins. Finally, different NAD hydrolase proteins also consume NAD+ while converting it into ADP-ribose or its cyclic counterpart. Some of these proteins, such as CD38, seem to be extensively involved in the immune response. Since NAD cannot be taken directly from food, NAD metabolism is essential, and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools. Because of the complex network of pathways in which NAD+ is essential, the important role of NAD+ and its key generating enzyme, NAMPT, in cancer is understandable. In the present work, we review the role of NAD+ and NAMPT in the ways that they may influence cancer metabolism, the immune system, stemness, aging, and cancer. Finally, we review some ongoing research on therapeutic approaches.

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“… 186 SIRT1 is also required for genomic stability and telomere elongation during cell reprogramming. 187 …”

Section: Nad + and Cancermentioning

confidence: 99%

NAD+ metabolism, stemness, the immune response, and cancer

Navas

Carnero

2021

Sig Transduct Target Ther

237

218

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“…Moreover, SIRT have been demonstrated as a factor that alters IPSCs reprogramming through metabolic changes in the cells. This is a gene family that may be amenable for modulation in order to improve reprogramming (Shin et al 2018). Another family of enzymes that is crucially involved in stem cell renewal, proliferation, and differentiation is that of NADPH oxidases, which mediate several basic cell processes trough modulation of redox status in embryo cell in their natural environment and also in culture expansion for therapy purposes.…”

Section: Mutations Induced During Reprogrammingmentioning

confidence: 99%

A Multilevel Approach to the Causes of Genetic Instability in Stem Cells

González

2022

Handbook of Stem Cell Therapy

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This chapter addresses the genetic instability in stem cells, a central feature that is an important determinant for the safety and effectiveness of cell-based therapies. First, DNA damage response mechanism and the gene network that regulates the DNA integrity homeostasis are revisited, focusing on relationship between genetic integrity and stemness maintenance. Also, several factors have been included that influence genetic instability in vivo, i.e., ROS generation and inflammation, and in vitro regarding cell isolation, culture conditions, i.e., oxygen levels and the use of feeder layers and different carriers, splitting procedures, passage number, etc. Telomere shortening, replicative senescence aneuploidy, and the senescence-associated secretory phenotype are different processes involved in deterioration of stem cells abilities for homing, reparability, and paracrine modulation. Moreover, less effective DNA repair upon senescence increases the propensity of developing tumors for stem cells that is one the main concerns related to genetic instability in stem cells. Nuclear organization and their determinants linked to chromosome aberrations and aneuploidy in stem cells and those epigenetic changes affecting stability are addressed. Differences between adipose, embryonic, and induced pluripotent stem cells are analyzed regarding to their ontogeny, changes in culture, and variation in proliferative capacity and stemness. The effect of reprogramming methods in genetic instability and variation in mutagenicity according to genes utilized for pluripotency induction, i.e., Yamanaka's factors and others, is discussed. Donor-related factors, i.e., age, smoking, and alcohol consumption, comorbidities, i.e., obesity, insulin resistance, diabetes, are mentioned for wide evaluation of genetic instability. The next years must witness consensus protocols that will contribute to control the effects of factors that alter stem cell genetic stability to increase the security and applicability of cell-based therapy.

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“…Sirtuins are proteins of the nicotinamide adeninedinucleotide-dependent deacetylases family (or silent information regulator 2 family—SIRT family), which are well-known for their role in many cellular processes [ 30 ] such as apoptosis [ 31 ], cell reprogramming [ 32 ], and DNA repair [ 33 ]. Sirtuins are also involved in cancer progression [ 34 ], ovarian aging [ 35 , 36 ], redox homeostasis [ 37 ], and glucose and lipid metabolism [ 38 ].…”

Section: Resveratrol Effects On Femalesmentioning

confidence: 99%

The Role of Resveratrol in Mammalian Reproduction

et al. 2020

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Resveratrol is one of the most investigated natural polyphenolic compounds and is contained in more than 70 types of plants and in red wine. The widespread interest in this polyphenol derives from its antioxidant, anti-inflammatory and anti-aging properties. Several studies have established that resveratrol regulates animal reproduction. However, the mechanisms of action and the potential therapeutic effects are still unclear. This review aims to clarify the role of resveratrol in male and female reproductive functions, with a focus on animals of veterinary interest. In females, resveratrol has been considered as a phytoestrogen due to its capacity to modulate ovarian function and steroidogenesis via sirtuins, SIRT1 in particular. Resveratrol has also been used to enhance aged oocyte quality and as a gametes cryo-protectant with mainly antioxidant and anti-apoptotic effects. In males, resveratrol enhances testes function and spermatogenesis through activation of the AMPK pathway. Furthermore, resveratrol has been supplemented to semen extenders, improving the preservation of sperm quality. In conclusion, resveratrol has potentially beneficial effects for ameliorating ovarian and testes function.

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Investigating the role of Sirtuins in cell reprogramming

Cited by 14 publications

References 99 publications

NAD+ metabolism, stemness, the immune response, and cancer

NAD+ metabolism, stemness, the immune response, and cancer

A Multilevel Approach to the Causes of Genetic Instability in Stem Cells

The Role of Resveratrol in Mammalian Reproduction

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