Sirtuin activators and inhibitors Villalba, José M.; Alcaín, Francisco J.
BioFactors (Oxford),
September/October 2012, Letnik:
38, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Sirtuins 1‐7 (SIRT1‐7) belong to the third class of deacetylase enzymes, which are dependent on NAD+ for activity. Sirtuins activity is linked to gene repression, metabolic control, apoptosis and ...cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities. We review here those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin‐based therapies. Almost all sirtuin activators have been described only for SIRT1. Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging‐related decline in heart function and neuronal loss. Due to its poor bioavailability, reformulated versions of resveratrol with improved bioavailability have been developed (resVida, Longevinex®, SRT501). Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379, among others) have been also developed to stimulate sirtuin activities more potently than resveratrol. Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide, among others). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases.
Abstract Background Although efforts continue to find new therapies to regenerate infarcted heart tissue, knowledge of the cellular and molecular mechanisms involved remains poor. Objectives This ...study sought to identify the origin of cardiac fibroblasts (CFs) in the infarcted heart to better understand the pathophysiology of ventricular remodeling following myocardial infarction (MI). Methods Permanent genetic tracing of epicardium-derived cell (EPDC) and bone marrow–derived blood cell (BMC) lineages was established using Cre/LoxP technology. In vivo gene and protein expression studies, as well as in vitro cell culture assays, were developed to characterize EPDC and BMC interaction and properties. Results EPDCs, which colonize the cardiac interstitium during embryogenesis, massively differentiate into CFs after MI. This response is disease-specific, because angiotensin II–induced pressure overload does not trigger significant EPDC fibroblastic differentiation. The expansion of epicardial-derived CFs follows BMC infiltration into the infarct site; the number of EPDCs equals that of BMCs 1 week post-infarction. BMC-EPDC interaction leads to cell polarization, packing, massive collagen deposition, and scar formation. Moreover, epicardium-derived CFs display stromal properties with respect to BMCs, contributing to the sustained recruitment of circulating cells to the damaged zone and the cardiac persistence of hematopoietic progenitors/stem cells after MI. Conclusions EPDCs, but not BMCs, are the main origin of CFs in the ischemic heart. Adult resident EPDC contribution to the CF compartment is time- and disease-dependent. Our findings are relevant to the understanding of post-MI ventricular remodeling and may contribute to the development of new therapies to treat this disease.
Abstract
Within four centuries of sunspot observations, the Maunder Minimum (MM) in 1645–1715 has been considered a unique grand minimum with weak solar cycles in group numbers of sunspots and ...hemispheric asymmetry in sunspot positions. However, the early part of the MM (1645–1659) is poorly understood in terms of its source records and has accommodated diverse reconstructions of the contemporaneous group number. This study identified their source records, classidied them in three different categories (datable observations, general descriptions, and misinterpreted records), and revised their data. On this basis, we estimated the yearly mean group number using the brightest star method, derived the active day fraction (ADF), reconstructed the sunspot number based on ADF, and compared them with proxy reconstructions from the tree-ring data sets. Our results revised the solar activity in the early MM downward in yearly mean group numbers using the brightest star method and upward in the active day fraction and sunspot number estimates. Our results are consistent with the proxy reconstruction for 1645–1654 and show more realistic values for 1657–1659 (against the unphysical negative sunspot number). These records have paid little attention to sunspot positions, except for Hevelius' report on a sunspot group in the northern solar hemisphere in 1652 April. Therefore, slight caveats are required to discuss if the sunspot positions are located purely in the southern solar hemisphere throughout the MM.
Olive Oil and the Hallmarks of Aging Fernández del Río, Lucía; Gutiérrez-Casado, Elena; Varela-López, Alfonso ...
Molecules (Basel, Switzerland),
01/2016, Letnik:
21, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Aging is a multifactorial and tissue-specific process involving diverse alterations regarded as the "hallmarks of aging", which include genomic instability, telomere attrition, epigenetic ...alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intracellular communication. Virtually all these hallmarks are targeted by dietary olive oil, particularly by virgin olive oil, since many of its beneficial effects can be accounted not only for the monounsaturated nature of its predominant fatty acid (oleic acid), but also for the bioactivity of its minor compounds, which can act on cells though both direct and indirect mechanisms due to their ability to modulate gene expression. Among the minor constituents of virgin olive oil, secoiridoids stand out for their capacity to modulate many pathways that are relevant for the aging process. Attenuation of aging-related alterations by olive oil or its minor compounds has been observed in cellular, animal and human models. How olive oil targets the hallmarks of aging could explain the improvement of health, reduced risk of aging-associated diseases, and increased longevity which have been associated with consumption of a typical Mediterranean diet containing this edible oil as the predominant fat source.
Skeletal muscle regeneration depends on the correct expansion of resident quiescent stem cells (satellite cells), a process that becomes less efficient with aging. Here, we show that mitochondrial ...dynamics are essential for the successful regenerative capacity of satellite cells. The loss of mitochondrial fission in satellite cells—due to aging or genetic impairment—deregulates the mitochondrial electron transport chain (ETC), leading to inefficient oxidative phosphorylation (OXPHOS) metabolism and mitophagy and increased oxidative stress. This state results in muscle regenerative failure, which is caused by the reduced proliferation and functional loss of satellite cells. Regenerative functions can be restored in fission-impaired or aged satellite cells by the re-establishment of mitochondrial dynamics (by activating fission or preventing fusion), OXPHOS, or mitophagy. Thus, mitochondrial shape and physical networking controls stem cell regenerative functions by regulating metabolism and proteostasis. As mitochondrial fission occurs less frequently in the satellite cells in older humans, our findings have implications for regeneration therapies in sarcopenia.
Display omitted
•Mitochondrial fission increases in satellite cells (SCs) after muscle injury•Mitochondrial fission boosts SC proliferation by inducing OXPHOS and proteostasis•DRP1 loss in SCs (genetically or during aging) impairs muscle regeneration•Normalizing mitochondrial dynamics in aged SCs restores muscle regeneration
Hong et al. illustrate that mitochondrial dynamics are required for tissue regeneration. Mitochondrial fission facilitates stem cell function via OXPHOS and mitophagy regulation. The genetic (or aging-related) loss of the mitochondrial fission regulator DRP1 in muscle stem cells blunts their proliferation and regenerative capacity, whereas DRP1 re-establishment rescues these defects.
Recent reports suggest that mammalian embryonic coronary endothelium (CoE) originates from the sinus venosus and ventricular endocardium. However, the contribution of extracardiac cells to CoE is ...thought to be minor and nonsignificant for coronary formation. Using classic (Wt1Cre
) and previously undescribed (G2-Gata4Cre
) transgenic mouse models for the study of coronary vascular development, we show that extracardiac septum transversum/proepicardium (ST/PE)-derived endothelial cells are required for the formation of ventricular coronary arterio–venous vascular connections. Our results indicate that at least 20% of embryonic coronary arterial and capillary endothelial cells derive from the ST/PE compartment. Moreover, we show that conditional deletion of the ST/PE lineage-specific Wilms’ tumor suppressor gene (Wt1) in the ST/PE ofG2-Gata4Cre
mice and in the endothelium of Tie2Cre
mice disrupts embryonic coronary transmural patterning, leading to embryonic death. Taken together, our results demonstrate that ST/PE-derived endothelial cells contribute significantly to and are required for proper coronary vascular morphogenesis.
The polyunsaturated nature of n-3 fatty acids makes them prone to oxidative damage. However, it is not clear if n-3 fatty acids are simply a passive site for oxidative attack or if they also modulate ...mitochondrial reactive oxygen species (ROS) production. The present study used fat-1 transgenic mice, that are capable of synthesizing n-3 fatty acids, to investigate the influence of increases in n-3 fatty acids and resultant decreases in the n-6:n-3 ratio on liver mitochondrial H(2)O(2) production and electron transport chain (ETC) activity. There was an increase in n-3 fatty acids and a decrease in the n-6:n-3 ratio in liver mitochondria from the fat-1 compared to control mice. This change was largely due to alterations in the fatty acid composition of phosphatidylcholine and phosphatidylethanolamine, with only a small percentage of fatty acids in cardiolipin being altered in the fat-1 animals. The lipid changes in the fat-1 mice were associated with a decrease (p<0.05) in the activity of ETC complex I and increases (p<0.05) in the activities of complexes III and IV. Mitochondrial H(2)O(2) production with either succinate or succinate/glutamate/malate substrates was also decreased (p<0.05) in the fat-1 mice. This change in H(2)O(2) production was due to a decrease in ROS production from ETC complex I in the fat-1 animals. These results indicate that the fatty acid changes in fat-1 liver mitochondria may at least partially oppose oxidative stress by limiting ROS production from ETC complex I.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We performed a meta-analysis to determine the changes induced by calorie restriction (CR) and bariatric surgery on human skeletal muscle mitochondria.
A systematic search of Medline and Web of ...Science was conducted. Controlled trials exploring CR (≥14 days) and mitochondrial function and/or content assessment were included. Moreover, studies analyzing weight loss following gastric surgery were included for comparison purposes. Human muscle data from 28 studies assessing CR (520 muscle samples) and from 10 studies assessing bariatric surgery (155 muscle samples) were analyzed in a random effect meta-analysis with three a priori chosen covariates.
We report a decrease (p < 0.05) (mean (95 % CI)) in maximal mitochondrial state 3 respiration in response to CR (−0.44 (−0.85, −0.03)) but not in response to surgery (−0.33 (−1.18, 0.52)). No changes in mitochondrial content were reported after CR (−0.05 (−0.12, 0.13)) or in response to surgery (0.23 (−0.05, 0.52)). Moreover, data from CR subjects showed a reduction in complex IV (CIV) activity (−0.29 (−0.56, −0.03)) but not in CIV content (−0.21 (−0.63, 0.22)). Similar results were obtained when the length of the protocol, the initial body mass index, and the estimated energy deficit were included in the model as covariates.
The observation of reduced maximal mitochondrial state 3, uncoupled respiration, and CIV activity without altering mitochondrial content suggests that, in human skeletal muscle, CR mainly modulates intrinsic mitochondrial function.
•Calorie restriction can improve metabolic health.•Calorie restriction does not alter mitochondrial volume in human skeletal muscle.•Calorie restriction decreases mitochondrial respiration and complex IV activity.•Bariatric surgery increases mitochondrial content and complex I-linked respiration.
Cytochrome b5 reductase 3 (CYB5R3) activates respiratory metabolism in cellular systems and exerts a prolongevity action in transgenic mice overexpressing this enzyme, mimicking some of the ...beneficial effects of calorie restriction. The aim of our study was to investigate the role of sex on metabolic adaptations elicited by CYB5R3 overexpression, and how key markers related with mitochondrial function are modulated in skeletal muscle, one of the major contributors to resting energy expenditure. Young CYB5R3 transgenic mice did not exhibit the striking adaptations in carbon metabolism previously detected in older animals. CYB5R3 was efficiently overexpressed and targeted to mitochondria in skeletal muscle from transgenic mice regardless sex. Overexpression significantly elevated NADH in both sexes, although differences were not statistically significant for NAD+, and increased the abundance of cytochrome c and the fission protein DRP-1 in females but not in males. Moreover, while mitochondrial biogenesis and function markers (as TFAM, NRF-1 and cleaved SIRT3) were markedly upregulated by CYB5R3 overexpression in females, a downregulation was observed in males. Ultrastructural changes were also highlighted, with an increase in the number of mitochondria per surface unit, and in the size of intermyofibrillar mitochondria in transgenic females compared with their wild-type controls. Our results support that CYB5R3 overexpression upregulates markers consistent with enhanced mitochondrial biogenesis and function, and increases mitochondrial abundance in skeletal muscle, producing most of these potentially beneficial actions in females.
Display omitted
•CYB5R3 overexpression in transgenic mice induces carbon metabolism adaptations in a sex specific manner.•Skeletal muscle is an optimal model to investigate cell-autonomous, CYB5R3-dependent mechanisms of metabolic regulation.•CYB5R3 upregulates skeletal muscle markers of mitochondrial function, dynamics and biogenesis only in females.•CYB5R3 overexpression increases the size and number of intermyofibrillar mitochondria in skeletal muscle from females.•CYB5R3 overexpression is a valuable model for investigating sexual dimorphic, and potentially novel, mechanisms of aging.
Development of the Myocardial Interstitium Pogontke, Cristina; Guadix, Juan A.; Ruiz‐Villalba, Adrián ...
Anatomical record (Hoboken, N.J. : 2007),
January 2019, 2019-01-00, 20190101, Letnik:
302, Številka:
1
Journal Article
PDF
