Treatment of FANCA Cells with Resveratrol and N-Acetylcysteine: A Comparative Study

Columbaro, Marta; Ravera, Silvia; Capanni, Cristina; Panfoli, Isabella; Cuccarolo, Paola; Stroppiana, Giorgia; Degan, Paolo; Cappelli, Enrico

doi:10.1371/journal.pone.0104857

Cited by 19 publications

(17 citation statements)

References 24 publications

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“…Protection against injury‐induced capillary degeneration by resveratrol has also been demonstrated (Lu et al ., ). Treatment of whole cells with resveratrol for some days partly restored the Fanconi anaemia mitochondrial metabolic activity while decreasing oxygen uptake in wild‐type cells (Columbaro et al ., ). The effects of N,N_‐dicyclohexylcarbodiimide and oligomycin are different as they act on the F o moiety in the lipid phase (Morelli et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina

Calzia

Oneto

Caicci

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSEThe rod outer segments (OS) of the retina are specialized organelles where phototransduction takes place. The mitochondrial electron transport complexes I-IV, cytochrome c and FoF1-ATP synthase are functionally expressed in the OS disks. Here, we have studied the effect of some polyphenolic compounds acting as inhibitors of mitochondrial ATPase/synthase activity on the OS ectopic FoF1-ATP synthase. The mechanism of apoptosis in the OS was also investigated studying the expression of cytochrome c, caspase 9 and 3 and Apaf-1. EXPERIMENTAL APPROACHWe prepared OS from fresh bovine retinae. Semi-quantitative Western blotting, confocal and electron microscopy, and cytofluorimetry were used along with biochemical analyses such as oximetry, ATP synthesis and hydrolysis. KEY RESULTSResveratrol and curcumin plus piperine inhibited ATP synthesis and oxygen consumption in the OS. Epigallocatechin gallate and quercetin inhibited ATP hydrolysis and oxygen consumption in the OS. Malondialdehyde and hydrogen peroxide were produced in respiring OS in the presence of substrates. Cytochrome c was located inside the disk membranes. Procaspase 9 and 3, as well as Apaf-1 were expressed in the OS. CONCLUSIONS AND IMPLICATIONSThese polyphenolic phytochemicals modulated the FoF1-ATP synthase activity of the the OS reducing production of reactive oxygen intermediates by the OS ectopic electron transport chain. Polyphenols decrease membrane peroxidation and cytochrome c release from disks, preventing the induction of caspase-dependent apoptosis in the OS Such effects are relevant in the design of protection against functional impairment of the OS following oxidative stress from exposure to intense illumination.

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Section: Discussionmentioning

confidence: 97%

Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina

Calzia

Oneto

Caicci

et al. 2015

British J Pharmacology

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“…After post‐fixation with 1% OsO4 in cacodylate buffer for 1 hr, pellets were dehydrated in an ethanol series and embedded in Epon resin. Ultrathin sections stained with uranyl‐acetate and lead citrate were observed using a Jeol Jem‐1011 transmission electron microscope (Columbaro et al, ).…”

Section: Methodsmentioning

confidence: 99%

Concentration‐dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells

Ravera

Cossu

Tappino

et al. 2017

Journal Cellular Physiology

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Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10-100-fold higher than the plasmatic concentration measured in patients. Here, we evaluated the biochemical, metabolic, and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines. We found that the response of wild-type cells to MET is concentration dependent. Low concentrations (15 and 150 µM) increase both oxidative phosphorylation and the oxidative stress response, acting on the AMPK/Sirt1 pathway, while the high concentration (1.5 mM) inhibits the respiratory chain, alters cell morphology, becoming toxic to the cells. In FA cells, MET was unable to correct the energetic/respiratory defect and did not improve the response to oxidative stress and DNA damage. By contrast, HL60 cells appear sensitive also at 150 μM. Our findings underline the importance of the MET concentration in evaluating the effect of this drug on cell metabolism and demonstrate that data obtained from in vitro experiments, that have used high concentrations of MET, cannot be readily translated into improving our understanding of the cellular effects of metformin when used in the clinical setting.

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“…To observe the ADPstimulated respiration rates, 0.08 mM ADP was added after pyruvate and malate and succinate addition. The respiratory rates were expressed as nmol O2/min/106 cells [12,13].…”

Section: Oxygen Consumption Measurementsmentioning

confidence: 99%

Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells

Salani

Ravera

Fabbi

et al. 2017

Cell Physiol Biochem

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Background: Sulfonylureas, such as glibenclamide, are antidiabetic drugs that stimulate beta-cell insulin secretion by binding to the sulfonylureas receptors (SURs) of adenosine triphosphate-sensitive potassium channels (K ATP ). Glibenclamide may be also cardiotoxic, this effect being ascribed to interference with the protective function of cardiac K ATP channels for which glibenclamide has high affinity. Prompted by recent evidence that glibenclamide impairs energy metabolism of renal cells, we investigated whether this drug also affects the metabolism of cardiac cells. Methods: The cardiomyoblast cell line H9c2 was treated for 24 h with glibenclamide or metformin, a known inhibitor of the mitochondrial respiratory chain. Cell viability was evaluated by sulforodhamine B assay. ATP and AMP were measured according to the enzyme coupling method and oxygen consumption by using an amperometric electrode, while Fo-F1 ATP synthase activity assay was evaluated by chemiluminescent method. Protein expression was measured by western blot. Results: Glibenclamide deregulated energy balance of H9c2 cardiomyoblasts in a way similar to that of metformin. It inhibited mitochondrial complexes I, II and III with ensuing impairment of oxygen consumption and ATP synthase activity, ATP depletion and increased AMPK phosphorylation. Furthermore, glibenclamide disrupted mitochondrial subcellular organization. The perturbation of mitochondrial energy balance was associated with enhanced anaerobic glycolysis, with increased activity of phosphofructo kinase, pyruvate kinase and lactic dehydrogenase. Interestingly, some additive effects of glibenclamide and metformin were observed. Conclusions: Glibenclamide deeply alters cell metabolism in cardiac cells by impairing mitochondrial organization and function. This may further explain the risk of cardiovascular events associated with the use of this drug, alone or in combination with metformin.

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Treatment of FANCA Cells with Resveratrol and N-Acetylcysteine: A Comparative Study

Cited by 19 publications

References 24 publications

Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina

Effect of polyphenolic phytochemicals on ectopic oxidative phosphorylation in rod outer segments of bovine retina

Concentration‐dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells

Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells

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