Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle
<i>Trans</i>-resveratrol (RSV) is a non-flavonoid polyphenol (stilbene) with numerous biological activities, such as anti-tumor activities. However, RSV is rapidly metabolized, which limits its therapeutic use. The availability of RSV analogues with similar activities for use in vivo is...
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MDPI AG
2023-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/7/3178 |
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| author | Mohamed Ksila Imen Ghzaiel Vivien Pires Taoufik Ghrairi Olfa Masmoudi-Kouki Norbert Latruffe Dominique Vervandier-Fasseur Anne Vejux Gérard Lizard |
| author_facet | Mohamed Ksila Imen Ghzaiel Vivien Pires Taoufik Ghrairi Olfa Masmoudi-Kouki Norbert Latruffe Dominique Vervandier-Fasseur Anne Vejux Gérard Lizard |
| author_sort | Mohamed Ksila |
| collection | DOAJ |
| description | <i>Trans</i>-resveratrol (RSV) is a non-flavonoid polyphenol (stilbene) with numerous biological activities, such as anti-tumor activities. However, RSV is rapidly metabolized, which limits its therapeutic use. The availability of RSV analogues with similar activities for use in vivo is therefore a major challenge. For this purpose, several isomeric analogues of RSV, aza-stilbenes (AZA-ST 1a–g), were synthesized, and their toxicities were characterized and compared to those of RSV on murine N2a neuronal cells using especially flow cytometric methods. All AZA-ST 1a–g have an inhibitory concentration 50 (IC50) between 11.3 and 25 µM when determined by the crystal violet assay, while that of RSV is 14.5 µM. This led to the characterization of AZA-ST 1a–g—induced cell death, compared to RSV, using three concentrations encompassing the IC50s (6.25, 12.5 and 25 µM). For AZA-ST 1a–g and RSV, an increase in plasma membrane permeability to propidium iodide was observed, and the proportion of cells with depolarized mitochondria measured with DiOC<sub>6</sub>(3) was increased. An overproduction of reactive oxygen species (ROS) was also observed on whole cells and at the mitochondrial level using dihydroethidium and MitoSox Red, respectively. However, only RSV induced a mode of cell death by apoptosis associated with a marked increase in the proportion of cells with condensed and/or fragmented nuclei (12.5 µM: 22 ± 9%; 25 µM: 80 ± 10%) identified after staining with Hoechst 33342 and which are characteristic of apoptotic cells. With AZA-ST, a slight but significant increase in the percentage of apoptotic cells was only detected with AZA-ST 1b (25 µM: 17 ± 1%) and AZA-ST 1d (25 µM: 26 ± 4%). Furthermore, only RSV induced significant cell cycle modifications associated with an increase in the percentage of cells in the S phase. Thus, AZA-ST 1a–g—induced cell death is characterized by an alteration of the plasma membrane, an induction of mitochondrial depolarization (loss of ΔΨm), and an overproduction of ROS, which may or may not result in a weak induction of apoptosis without modification of the distribution of the cells in the different phases of the cell cycle. |
| first_indexed | 2024-03-11T05:30:15Z |
| format | Article |
| id | doaj.art-ecc74686b46542f4995ed44e49f6e911 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T05:30:15Z |
| publishDate | 2023-04-01 |
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| spelling | doaj.art-ecc74686b46542f4995ed44e49f6e9112023-11-17T17:14:46ZengMDPI AGMolecules1420-30492023-04-01287317810.3390/molecules28073178Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell CycleMohamed Ksila0Imen Ghzaiel1Vivien Pires2Taoufik Ghrairi3Olfa Masmoudi-Kouki4Norbert Latruffe5Dominique Vervandier-Fasseur6Anne Vejux7Gérard Lizard8Team ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA7270/Inserm, University of Bourgogne, 21000 Dijon, FranceTeam ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA7270/Inserm, University of Bourgogne, 21000 Dijon, FranceTeam ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA7270/Inserm, University of Bourgogne, 21000 Dijon, FranceLaboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules, (LR18ES03), Department of Biology, Faculty of Sciences, University Tunis El Manar, Tunis 2092, TunisiaLaboratory of Neurophysiology, Cellular Physiopathology and Valorisation of Biomolecules, (LR18ES03), Department of Biology, Faculty of Sciences, University Tunis El Manar, Tunis 2092, TunisiaTeam ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA7270/Inserm, University of Bourgogne, 21000 Dijon, FranceTeam OCS, Institute of Molecular Chemistry (ICMUB UMR CNRS 6302), University of Bourgogne, 21000 Dijon, FranceTeam ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA7270/Inserm, University of Bourgogne, 21000 Dijon, FranceTeam ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ EA7270/Inserm, University of Bourgogne, 21000 Dijon, France<i>Trans</i>-resveratrol (RSV) is a non-flavonoid polyphenol (stilbene) with numerous biological activities, such as anti-tumor activities. However, RSV is rapidly metabolized, which limits its therapeutic use. The availability of RSV analogues with similar activities for use in vivo is therefore a major challenge. For this purpose, several isomeric analogues of RSV, aza-stilbenes (AZA-ST 1a–g), were synthesized, and their toxicities were characterized and compared to those of RSV on murine N2a neuronal cells using especially flow cytometric methods. All AZA-ST 1a–g have an inhibitory concentration 50 (IC50) between 11.3 and 25 µM when determined by the crystal violet assay, while that of RSV is 14.5 µM. This led to the characterization of AZA-ST 1a–g—induced cell death, compared to RSV, using three concentrations encompassing the IC50s (6.25, 12.5 and 25 µM). For AZA-ST 1a–g and RSV, an increase in plasma membrane permeability to propidium iodide was observed, and the proportion of cells with depolarized mitochondria measured with DiOC<sub>6</sub>(3) was increased. An overproduction of reactive oxygen species (ROS) was also observed on whole cells and at the mitochondrial level using dihydroethidium and MitoSox Red, respectively. However, only RSV induced a mode of cell death by apoptosis associated with a marked increase in the proportion of cells with condensed and/or fragmented nuclei (12.5 µM: 22 ± 9%; 25 µM: 80 ± 10%) identified after staining with Hoechst 33342 and which are characteristic of apoptotic cells. With AZA-ST, a slight but significant increase in the percentage of apoptotic cells was only detected with AZA-ST 1b (25 µM: 17 ± 1%) and AZA-ST 1d (25 µM: 26 ± 4%). Furthermore, only RSV induced significant cell cycle modifications associated with an increase in the percentage of cells in the S phase. Thus, AZA-ST 1a–g—induced cell death is characterized by an alteration of the plasma membrane, an induction of mitochondrial depolarization (loss of ΔΨm), and an overproduction of ROS, which may or may not result in a weak induction of apoptosis without modification of the distribution of the cells in the different phases of the cell cycle.https://www.mdpi.com/1420-3049/28/7/3178apoptosisaza-stilbenescell deathcell cycleflow cytometryimine analogs of <i>trans</i>-resveratrol |
| spellingShingle | Mohamed Ksila Imen Ghzaiel Vivien Pires Taoufik Ghrairi Olfa Masmoudi-Kouki Norbert Latruffe Dominique Vervandier-Fasseur Anne Vejux Gérard Lizard Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle Molecules apoptosis aza-stilbenes cell death cell cycle flow cytometry imine analogs of <i>trans</i>-resveratrol |
| title | Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle |
| title_full | Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle |
| title_fullStr | Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle |
| title_full_unstemmed | Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle |
| title_short | Characterization of Cell Death Induced by Imine Analogs of Trans-Resveratrol: Induction of Mitochondrial Dysfunction and Overproduction of Reactive Oxygen Species Leading to, or Not, Apoptosis without the Increase in the S-Phase of the Cell Cycle |
| title_sort | characterization of cell death induced by imine analogs of trans resveratrol induction of mitochondrial dysfunction and overproduction of reactive oxygen species leading to or not apoptosis without the increase in the s phase of the cell cycle |
| topic | apoptosis aza-stilbenes cell death cell cycle flow cytometry imine analogs of <i>trans</i>-resveratrol |
| url | https://www.mdpi.com/1420-3049/28/7/3178 |
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