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Influence of resveratrol in chronological life span (CLS) of S. cerevisiae at different glucose concentrations. The CLS of S. cerevisiae was assayed in minimal medium (SC) supplemented with: a 10% glucose; b 2% glucose; c 0.5% glucose. Results represent mean values ± SEM from 4 independent experiments, which includes mean values of 3 technical repetitions. Statistical significance was calculated by repeated measures one-way ANOVA followed by Dunnett’s test (*P < 0.05 vs. control)
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A broad range of health benefits have been attributed to resveratrol (RSV) supplementation in mammalian systems, including the increases in longevity. Nonetheless, despite the growing number of studies performed with RSV, the molecular mechanism by which it acts still remains unknown. Recently, it has been proposed that inhibition of the oxidative...
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... The MMP indicates redox transformations linked to the Krebs cycle, acting as an intermediary energy state, which is used by ATP synthase to produce ATP (Zorova et al., 2018). Therefore, the MMP measurement can help to understand the inhibitors role in oxidative phosphorylation (Ramos-Gomez et al., 2017). Based on these facts, our data showed inhibitors mitochondrial damage either alone or in mixture, resulting in Krebs cycle impairment and reduced ATP synthesis. ...
Lignocellulosic material is the most prominent carbon source to obtain profitable biotechnological processes, but compounds like furfural and acetic acid are highly toxic to yeasts. Nonetheless, research about the molecular mechanism of furfural and acetic acid toxicity is still scarce in yeasts like Scheffersomyces stipitis . Thus, this work aimed to identify the role of furfural and acetic acid on S. stipitis in bioenergetic and fermentation parameters. Here, we provide evidence that furfural and acetic acid caused a cell growth delay and extension of the lag phase. The mitochondrial membrane potential decreased in all treatments without differences among inhibitors or concentrations. Interestingly, the reactive oxygen species increased when the inhibitors concentrations were from 0.1 to 0.3% (v/v). The glycolytic flux was not significantly ( p >0.05) altered by acetic acid, but furfural caused different effects. The ethanol production decreased significantly (4.32 g/L in furfural and 5.06 g/L in acetic acid) compared to the control (26.3 g/L). At the same time, biomass was not significantly different in almost all treatments compared to the control. This study provides additional understanding of the effects of furfural and acetic acid at mitochondrial level in a pentose-fermenting yeast like S. stipitis .
... This stunted growth phenotype in ncr1Δcyb5Δ is present at log-phase whereby exponential growth is slowed, diauxic shift from fermentation to respiration occurs earlier than control, and the culture arrests in growth entering the G0 state at a significantly lower cell density than control. This growth pattern is typical in cells missing essential nutrients such as nitrogen, phosphate, or glucose (Gray et al. 2004;Smets et al. 2010;Ramos-Gomez et al. 2017). Single mutant strains ncr1Δ and cyb5Δ each displayed a growth curve phenotype similar to that of wild type, which was consistent with previously reported results (Truan et al. 1994;Malathi et al. 2004). ...
Niemann-Pick type C (NP-C) disease is a rare lysosomal storage disease caused by mutations in NPC1 (95% cases) or NPC2 (5% cases). These proteins function together in cholesterol egress from the lysosome, whereby upon mutation, cholesterol and other lipids accumulate causing major pathologies. However, it is not fully understood how cholesterol is transported from NPC1 residing at the lysosomal membrane to the endoplasmic reticulum and plasma membrane. The yeast orthologue of NPC1, Niemann-Pick type C related protein-1 (Ncr1), functions similarly to NPC1; when transfected into a mammalian cell lacking NPC1, Ncr1 rescues the diagnostic hallmarks of cholesterol and sphingolipid accumulation. Here we aimed to identify and characterise protein-protein interactions (PPIs) with the yeast Ncr1 protein. A genome-wide split-ubiquitin membrane yeast two-hybrid (MYTH) protein interaction screen identified 11 ER membrane-localised, full-length proteins interacting with Ncr1 at the lysosomal/vacuolar membrane. These highlight the importance of ER-vacuole membrane interface and include PPIs with the Cyb5/Cbr1 electron transfer system, the ceramide synthase complex and the Sec61/Sbh1 protein translocation complex. These PPIs were not detected in a sterol auxotrophy condition and thus depend on normal sterol metabolism. To provide biological context for the Ncr1-Cyb5 PPI, a yeast strain lacking this PPI (via gene deletions) exhibited altered levels of sterols and sphingolipids including increased levels of glucosylceramide that mimic NP-C disease. Overall, the results herein provide new physical and genetic interaction models to further use the yeast model of NP-C disease to better understand human NP-C disease.
... Resveratrol shows cytotoxic and pro-oxidant effects on hepatic cells depending on its concentration and time of exposure [12]. Moreover, it shortens the lifespan of Saccharomyces cerevisiae by a pro-oxidant mechanism [13]. ...
An 8-week feeding trial was carried out to evaluate the effects of grapevine (Vitis vinifera) leaf extract (GLE) on the growth, oxidative enzymatic activities, immunity, and expression of antioxidant genes in zebrafish (Danio rerio). Three hundred and sixty zebrafish were supplied and fed with different levels of GLE: 0, 0.5, 1, and 2 g kg−1. The dietary administration of 1 g kg−1 of GLE significantly increased growth parameters in fish. Fish fed diets with GLE showed increased total protein. The total Ig and lysozyme activity significantly changed in the whole-body serum, but not in skin mucus. GLE significantly increased Catalase (CAT), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GPx) activities compared to the control diet. GLE treatments caused a significant decrease in the malondialdehyde (MDA) content. In the skin mucus, only CAT and SOD activities significantly increased. The highest expression of Toll-like receptor-1 (TLR-1) and Tumor Necrosis Factor-α (TNFα) genes was achieved in fish fed 2 g kg−1 of GLE. CAT and SOD gene expressions were significantly higher in fish fed 1 and 2 g kg−1 of GLE. GPx gene expression was significantly higher in fish fed 1 g kg−1 of GLE. In conclusion, the results of the present study revealed that GLE affects growth performance and regulates antioxidant and immune gene expression. The determination of the optimum dosage merits further research.
... The hypothesis that resveratrol impairs mitochondrial respiration as its main target has gained attention in the last years and could explain its toxic and antioxidant properties . In this regard, it has been reported that resveratrol disturbs the electron flux between complex I and complex III of the electron transport chain (ETC), impairing mitochondrial respiration (Ramos-Gomez et al., 2017). Based on these data, two molecular mechanisms to explain the pro-oxidant properties of resveratrol have been proposed. ...
... Importantly, a diet-dependent effect of phenotypes displayed by resveratrol supplementation has also been documented (Olivares-Marin et al., 2019). For example, resveratrol exhibits a glucose-dependent effect in chronological aging (Ramos-Gomez et al., 2017), cellular viability , mitochondrial respiration , and hydrogen peroxide release (Ramos-Gomez et al., 2017) in S. cerevisiae. In the Apc Min mice, a model of colorectal carcinogenesis, resveratrol treatment (0.00007%) decreased adenoma number per mouse in a high-fat diet but not in a standard diet (Cai et al., 2015). ...
... Importantly, a diet-dependent effect of phenotypes displayed by resveratrol supplementation has also been documented (Olivares-Marin et al., 2019). For example, resveratrol exhibits a glucose-dependent effect in chronological aging (Ramos-Gomez et al., 2017), cellular viability , mitochondrial respiration , and hydrogen peroxide release (Ramos-Gomez et al., 2017) in S. cerevisiae. In the Apc Min mice, a model of colorectal carcinogenesis, resveratrol treatment (0.00007%) decreased adenoma number per mouse in a high-fat diet but not in a standard diet (Cai et al., 2015). ...
The antioxidant phenotype caused by resveratrol has been recognized as a key piece in the health benefits exerted by this phytochemical in diseases related to aging. It has recently been proposed that a mitochondrial pro-oxidant mechanism could be the cause of resveratrol antioxidant properties. In this regard, the hypothesis that resveratrol impedes electron transport to complex III of the electron transport chain as its main target suggests that resveratrol could increase reactive oxygen species (ROS) generation through reverse electron transport or by the semiquinones formation. This idea also explains that cells respond to resveratrol oxidative damage, inducing their antioxidant systems. Moreover, resveratrol pro-oxidant properties could accelerate the aging process, according to the free radical theory of aging, which postulates that organisms age due to the accumulation of the harmful effects of ROS in cells. Nonetheless, there is no evidence linking the chronological lifespan (CLS) shorten occasioned by resveratrol with a pro-oxidant mechanism. Hence, this study aimed to evaluate whether resveratrol shortens the CLS of Saccharomyces cerevisiae due to a pro-oxidant activity. Herein, we provide evidence that supplementation with 100 μM of resveratrol at 5% glucose: 1) shorted the CLS of ctt1∆ and yap1∆ strains; 2) decreased ROS levels and increased the catalase activity in WT strain; 3) maintained unaffected the ROS levels and did not change the catalase activity in ctt1∆ strain; 4) lessened the exponential growth of ctt1∆ strain, which was restored with the adding of reduced glutathione. These results indicate that resveratrol decreases CLS by a pro-oxidant mechanism.
... The enigma of the dichotomic and pro-aging effects of RSV Natural RSV captured widespread scientific and public interest due to its reported anti-cancer [13] and antiaging effects [14], supported by further longevity demonstrations in other organisms [15][16][17][18]. However, unlike widely perceived, RSV decreased the normal (chronological) lifespan in yeast [19][20][21], and it extended only the replicative lifespan which is calculated based on the number of daughter cells an individual yeast mother cell produces before dying [14]. Moreover, the replicative lifespan effect of RSV in yeast was immediately questioned as it was not reproducible [22] indicating that the mechanism of action of the anti-and proaging effects of RSV is not yet understood. ...
... Similarly, higher doses of RSV decreased the normal lifespan in mice as well (mice died within 3-4 months) [23] and resulted in kidney toxicity in rats [24]. Consistent with the pro-aging effects of RSV [19][20][21]23], it is known to evoke toxic effects such as induction of neurite degeneration [25], atherosclerosis [26], premature senescence [27][28][29][30][31][32], genotoxicity [33][34][35][36][37][38], and inhibition of hippocampal neurogenesis [39]. These observations suggest that the mechanism of action of RSV that promoted longevity in other organisms [15][16][17][18] is not yet completely understood. ...
... Later studies also indicated a direct link between trans-RSV and 5′ adenosine monophosphate-activated protein kinase (AMPK) and SIRT1 by showing RSV's inhibitory effect on several phosphodiesterases (PDE) that increased cyclic AMP (cAMP) levels to enhance the intracellular Ca 2+ to activate Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ), which phosphorylates AMPK, finally leading to SIRT1 activation [200,201]. Although, the attempts to modulate the activity and specificity of RSV through different targets or signaling cascades failed to reproduce the complete spectrum of its activity, [202,203] highlighting some technical problems associated with the "Fluor-de-Lys" substrate (FdL) assay used to determine RSV-mediated SIRT1 activation [20,22,204,205], subsequent works finally concluded that trans-RSV is indeed a direct activator of SIRT1 [206][207][208] with a potency of RSV against SIRT1 in the FdL assay (EC 50~3 0-100 μM) [14,207] whereas the Km value of SIRT1 for NAD + was found to be 94 ± 5 μM [203]. Finally, patients who received 500 mg/day RSV demonstrated the activation of SIRT1 in peripheral blood mononuclear cell (PBMC), suggesting that oral administration of higher doses of RSV achieve sufficient cellular concentrations to activate SIRT1 (≥ 30 μM) in humans as well [209]. ...
Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADP-ribose polymerase 1 (PARP1), a major determinant of cellular NAD+-dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the auto-poly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1-mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention.
... Contrastingly, there have been multiple reports stating resveratrol failed to extend lifespan in C. elegans, fruit flies [23], and mice [24] despite its benefits on oxidative resistance and other pro-aging effects. Some recent experiments done with budding yeast showed that resveratrol not just failed to do any significant improvements in anti-oxidant activity but also some reduction in CLS was observed [25,26]. These results confirmed our previous experiments where resveratrol failed to improve mitochondrial membrane potential and induced no changes in ATP and ROS levels [27]. ...
Extension of lifespan and amelioration of aging-associated phenotypes have been targets of many studies. Some of the established methods of increasing lifespan including dietary restriction and genetic manipulation are difficult to apply to humans, and their side effects are hard to predict. For that reason, it is important to discover compounds that can mimic the anti-aging actions or induce lifespan extension through different metabolisms within the cell. Here we summarize the recent studies to test various types of compounds and materials using budding yeast that show potential anti-aging effects. Keywords: Anti-aging agent, Budding yeast, Lifespan extension, Chronological lifespan, Replicative lifespan
... Resveratrol might have a hormetic effect, which first stimulates ROS generation and later ROS elimination systems (Plauth et al. 2016). It has recently been found that resveratrol acts as a pro-oxidant molecule inducing mitochondrial dysfunction and ROS generation on yeast; however, this effect is glucose-dependent (Ramos-Gomez et al. 2017). ...
Humans and other organisms show age-related signs of deterioration, which makes aging an interesting process to study. In the present work, we review the anti-aging evidence of several of the most promising natural compounds. Quercetin, rapamycin, resveratrol, spermidine, curcumin or sulforaphane administration increase longevity and stress resistance in model organisms such as yeasts, nematodes, flies and mice. Even more, rapamycin, resveratrol, and curcumin are currently in preclinical tests on the Interventions Testing Program of the National Institute on Aging due to their encouraging results in model organisms. The potential mechanisms underlying the beneficial effects of these compounds are briefly described.
... In this regard, resveratrol supplementation at 10, 30, 50, and 100 μM into S. cerevisiae cultures grown in 10% of glucose diminished H 2 O 2 release, while in 2% of glucose, H 2 O 2 release was diminished only at 100 μM, and in 0.5% of glucose, resveratrol (10 μM) promoted a higher release of H 2 O 2 (Ramos- Gomez et al., 2017). Therefore, resveratrol may have an antioxidant effect at the physiological level or a pro-oxidant cytotoxic effect, depending on the concentrations of resveratrol and the energy state of the cell, suggesting that by modifying the energetic state of the cell, it is possible to increase the cytotoxic effect of resveratrol. ...
... Yeast cultures grown at a high glucose level (10% of glucose) exhibited an increase in basal respiration and maximal respiratory capacity as the resveratrol concentration increased. At a standard glucose level (2% of glucose), resveratrol affects the respiratory capacity only at 100 μM, while at a low glucose level (0.5% of glucose), resveratrol supplementation inhibited the respiratory capacity of S. cerevisiae at all concentrations tested, supporting the hypothesis that the primary target of resveratrol is the inhibition of cellular respiration (Ramos- Gomez et al., 2017). ...
... the cell viability of cells at high glucose concentrations (10% of glucose) when cultures were supplemented with 1,000 μM of resveratrol ( ). Furthermore, a reduction in the chronological lifespan of S. cerevisiae was observed when the same concentration (100 μM) of resveratrol was supplemented in yeast cultures grown with 2 and 0.5% of glucose (Ramos- Gomez et al., 2017). In addition, as the resveratrol concentration increased and the carbon concentration diminished, the cytotoxic effect of resveratrol was more evident Ramos-Gomez et al., 2017). ...
Resveratrol is a phytochemical that may promote health. However, it has also been reported to be a toxic compound. The molecular mechanism by which resveratrol acts remains unclear. The inhibition of the oxidative phosphorylation (OXPHOS) pathway appears to be the molecular mechanism of resveratrol. Taking this into account, we propose that the cytotoxic properties of resveratrol depend on the energy (e.g., carbohydrates, lipids, and proteins) availability in the cells. In this regard, in a condition with low energy accessibility, resveratrol could enhance ATP starvation to lethal levels. In contrast, when cells are supplemented with high quantities of energy and resveratrol, the inhibition of OXPHOS might produce a low‐energy environment, mimicking the beneficial effects of caloric restriction. This review suggests that investigating a possible complex relationship between caloric intake and the differential effects of resveratrol on OXPHOS may be justified.
Practical applications
A low‐calorie diet accompanied by significant levels of resveratrol might modify cellular bioenergetics, which could impact cellular viability and enhance the anti‐cancer properties of resveratrol.
... Despite a number of studies that demonstrate the lifeextending activity of resveratrol, its anti-ageing properties are still controversial due to the growing number of reports to the contrary. Recently, Ramos-Gomez and oth-ers (Ramos-Gomez et al., 2017) described that resveratrol caused mitochondrial dysfunction and reduction in the chronological life-span of Saccharomyces cerevisiae. Similarly, it is known that dietary resveratrol does not extend the life span of the mosquito Anopheles stephensi (Johnson & Riehle, 2015) nor Drosophila melanogaster and does not influence gene expression of longevity-associated and antioxidant enzymes (Staats et al., 2018). ...
Resveratrol is a polyphenol which is abundant in grape skin and seeds. Sources of resveratrol in food also include wine, berries, and peanuts. This compound displays many properties including activity against glycation, oxidative stress, inflammation, neurodegeneration, several types of cancer, as well as aging. Due to the fact that resveratrol is generally well-tolerated, it is believed to be a promising compound in preventing many diseases such as diabetes and associated complications. Unfortunately, this compound exhibits low bioavailability and solubility. The aim of this review is to summarize recent information from in vitro and in vivo studies on animals and humans on the multiple effects of resveratrol on health and benefits of its intake.
... This protocol is only used to screen a phenotype, so the specific effects on fermentation and mitochondrial respiration must be confirmed. We recommend the quantification of mitochondrial respiration by oxygen consumption assays 13,14 , while fermentation can be determined by the accumulation of byproducts such as acetate, succinate, glycerol, and ethanol 9 . ...
... Finally, studying the log phase using the exponential growth equation is a consistent method to understand the influence of mitochondrial respiration or fermentation on a specific compound or environment. As a proof of concept, quantification of growth in the exponential phase demonstrated that RSV specifically affects respiratory growth 13,14 . Here, growth served as a valuable tool to identify that RIM15 deletion likely improves fermentative metabolism by partial inhibition of the respiration capacity in S. cerevisiae 9 . ...
