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Article ; Online: Effects of Dichlorvos on cardiac cells: Toxicity and molecular mechanism of action

Ben Salem, Intidhar / Boussabbeh, Manel / Pires Da Silva, Julie / Saidi, Nour Elhouda / Abid-Essefi, Salwa / Lemaire, Christophe

Chemosphere. 20232023 July 18, Apr. 18, v. 330 p.138714-

2023

Abstract: In this study we aimed to understand the underlying mechanism of Dichlorvos-induced toxicity in cardiac cells. For this end, cells were treated by 170 μM of Dichlorvos (DDVP) (corresponding to the IC50) and molecular events were monitored by flow ... ...

Abstract	In this study we aimed to understand the underlying mechanism of Dichlorvos-induced toxicity in cardiac cells. For this end, cells were treated by 170 μM of Dichlorvos (DDVP) (corresponding to the IC50) and molecular events were monitored by flow cytometry and western blotting. We have first demonstrated that cell exposure to DDVP for 24 h induced cell death by necroptosis. In fact, cell treatment with DDVP upregulated RIP1 expression and we have shown that chemical inhibition of RIP1 kinase activity by necrostatin-1 (Nec-1) greatly prevented from the induced cell death. Besides, we have demonstrated that, while there was no observed cell death following short exposure to DDVP (6 h), autophagy was enhanced, as proven by the increase in the level of both Beclin-1 and LC3-II and the accumulation of the CytoID® autophagy detection probe. Besides, when autophagy was inhibited by chloroquine (CQ) the percentage of necroptosis was significantly increased, suggesting that autophagy acts to protect cardiac cells against the toxicity induced by this pesticide. Concurrently, we have shown that the inhibition of the deacetylase sirtuin 1 (SIRT1) by EX527 or its knockdown by siRNA significantly increased DDVP-induced necroptosis, whereas when SIRT1 was activated by resveratrol (RSV) a significant decrease in DDVP-induced cell death was observed. In addition, we revealed that when the autophagy was inhibited by CQ, we can't reveal the protective effect of RSV anymore. Altogether, these results suggest that activation of SIRT1 protects cardiac cells from the toxicity of DDVP through an autophagy-dependent pathway.
Keywords	autophagy ; chloroquine ; dichlorvos ; flow cytometry ; inhibitory concentration 50 ; mechanism of action ; necroptosis ; protective effect ; resveratrol ; sirtuins ; toxicity ; ER stress ; SIRT1 ; DDVP ; RSV ; NEC-1 ; CQ
Language	English
Dates of publication	2023-0418
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2023.138714
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Article ; Online: Effects of Dichlorvos on cardiac cells: Toxicity and molecular mechanism of action.

Ben Salem, Intidhar / Boussabbeh, Manel / Pires Da Silva, Julie / Saidi, Nour Elhouda / Abid-Essefi, Salwa / Lemaire, Christophe

Chemosphere

2023 Volume 330, Page(s) 138714

Abstract	In this study we aimed to understand the underlying mechanism of Dichlorvos-induced toxicity in cardiac cells. For this end, cells were treated by 170 μM of Dichlorvos (DDVP) (corresponding to the IC50) and molecular events were monitored by flow cytometry and western blotting. We have first demonstrated that cell exposure to DDVP for 24 h induced cell death by necroptosis. In fact, cell treatment with DDVP upregulated RIP1 expression and we have shown that chemical inhibition of RIP1 kinase activity by necrostatin-1 (Nec-1) greatly prevented from the induced cell death. Besides, we have demonstrated that, while there was no observed cell death following short exposure to DDVP (6 h), autophagy was enhanced, as proven by the increase in the level of both Beclin-1 and LC3-II and the accumulation of the CytoID® autophagy detection probe. Besides, when autophagy was inhibited by chloroquine (CQ) the percentage of necroptosis was significantly increased, suggesting that autophagy acts to protect cardiac cells against the toxicity induced by this pesticide. Concurrently, we have shown that the inhibition of the deacetylase sirtuin 1 (SIRT1) by EX527 or its knockdown by siRNA significantly increased DDVP-induced necroptosis, whereas when SIRT1 was activated by resveratrol (RSV) a significant decrease in DDVP-induced cell death was observed. In addition, we revealed that when the autophagy was inhibited by CQ, we can't reveal the protective effect of RSV anymore. Altogether, these results suggest that activation of SIRT1 protects cardiac cells from the toxicity of DDVP through an autophagy-dependent pathway.
MeSH term(s)	Dichlorvos/toxicity ; Sirtuin 1/metabolism ; Cell Death ; Resveratrol ; Autophagy
Chemical Substances	Dichlorvos (7U370BPS14) ; Sirtuin 1 (EC 3.5.1.-) ; Resveratrol (Q369O8926L)
Language	English
Publishing date	2023-04-18
Publishing country	England
Document type	Journal Article
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2023.138714
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Article ; Online: Triazole fungicide tebuconazole induces apoptosis through ROS-mediated endoplasmic reticulum stress pathway.

Ben Othmène, Yosra / Monceaux, Kevin / Belhadef, Anissa / Karoui, Ahmed / Ben Salem, Intidhar / Boussabbeh, Manel / Abid-Essefi, Salwa / Lemaire, Christophe

Environmental toxicology and pharmacology

2022 Volume 94, Page(s) 103919

Abstract: Tebuconazole (TEB) is a common triazole fungicide that has been widely applied in the treatment of fungal diseases. It is reported that TEB could exert harmful effects on mammals' health. However, the molecular mechanism involved in TEB toxicity remain ... ...

Abstract	Tebuconazole (TEB) is a common triazole fungicide that has been widely applied in the treatment of fungal diseases. It is reported that TEB could exert harmful effects on mammals' health. However, the molecular mechanism involved in TEB toxicity remain undefined. Our study aimed to investigate the mechanisms of TEB-induced toxicity in intestinal cells. We found that TEB stimulates apoptosis through the mitochondrial pathway. Additionally, TEB triggers endoplasmic reticulum (ER) stress as demonstrated by the activation of the three arms of unfolded protein response (UPR). The incubation with the chemical chaperone 4-phenylbutyrate (4-PBA) alleviated ER stress and reduced TEB-induced apoptosis, suggesting that ER stress plays an important role in mediating TEB-induced toxicity. Furthermore, inhibition of ROS by N-acetylcysteine (NAC) inhibited TEB-induced ER stress and apoptosis. Taken together, these findings suggest that TEB exerts its toxic effects in HCT116 cells by inducing apoptosis through ROS-mediated ER stress and mitochondrial apoptotic pathway.
MeSH term(s)	Animals ; Apoptosis ; Endoplasmic Reticulum Stress ; Fungicides, Industrial/toxicity ; Mammals/metabolism ; Reactive Oxygen Species/metabolism ; Triazoles/toxicity
Chemical Substances	Fungicides, Industrial ; Reactive Oxygen Species ; Triazoles ; tebuconazole (401ATW8TRW)
Language	English
Publishing date	2022-06-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1318302-3
ISSN	1872-7077 ; 1382-6689
ISSN (online)	1872-7077
ISSN	1382-6689
DOI	10.1016/j.etap.2022.103919
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Article ; Online: Coalescence 2.0: a multiple branching of recent theoretical developments and their applications.

Tellier, Aurélien / Lemaire, Christophe

Molecular ecology

2014 Volume 23, Issue 11, Page(s) 2637–2652

Abstract: Population genetics theory has laid the foundations for genomic analyses including the recent burst in genome scans for selection and statistical inference of past demographic events in many prokaryote, animal and plant species. Identifying SNPs under ... ...

Abstract	Population genetics theory has laid the foundations for genomic analyses including the recent burst in genome scans for selection and statistical inference of past demographic events in many prokaryote, animal and plant species. Identifying SNPs under natural selection and underpinning species adaptation relies on disentangling the respective contribution of random processes (mutation, drift, migration) from that of selection on nucleotide variability. Most theory and statistical tests have been developed using the Kingman coalescent theory based on the Wright-Fisher population model. However, these theoretical models rely on biological and life history assumptions which may be violated in many prokaryote, fungal, animal or plant species. Recent theoretical developments of the so-called multiple merger coalescent models are reviewed here (Λ-coalescent, beta-coalescent, Bolthausen-Sznitman, Ξ-coalescent). We explain how these new models take into account various pervasive ecological and biological characteristics, life history traits or life cycles which were not accounted in previous theories such as (i) the skew in offspring production typical of marine species, (ii) fast adapting microparasites (virus, bacteria and fungi) exhibiting large variation in population sizes during epidemics, (iii) the peculiar life cycles of fungi and bacteria alternating sexual and asexual cycles and (iv) the high rates of extinction-recolonization in spatially structured populations. We finally discuss the relevance of multiple merger models for the detection of SNPs under selection in these species, for population genomics of very large sample size and advocate to potentially examine the conclusion of previous population genetics studies.
MeSH term(s)	Animals ; Genetic Drift ; Genetic Variation ; Genetics, Population/methods ; Linkage Disequilibrium ; Models, Genetic ; Polymorphism, Single Nucleotide ; Selection, Genetic
Language	English
Publishing date	2014-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.12755
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Article: Coalescence 2.0: a multiple branching of recent theoretical developments and their applications

Tellier, Aurélien / Lemaire, Christophe

Molecular ecology. 2014 June, v. 23, no. 11

2014

Abstract	Population genetics theory has laid the foundations for genomic analyses including the recent burst in genome scans for selection and statistical inference of past demographic events in many prokaryote, animal and plant species. Identifying SNPs under natural selection and underpinning species adaptation relies on disentangling the respective contribution of random processes (mutation, drift, migration) from that of selection on nucleotide variability. Most theory and statistical tests have been developed using the Kingman coalescent theory based on the Wright‐Fisher population model. However, these theoretical models rely on biological and life history assumptions which may be violated in many prokaryote, fungal, animal or plant species. Recent theoretical developments of the so‐called multiple merger coalescent models are reviewed here (Λ‐coalescent, beta‐coalescent, Bolthausen‐Sznitman, Ξ‐coalescent). We explain how these new models take into account various pervasive ecological and biological characteristics, life history traits or life cycles which were not accounted in previous theories such as (i) the skew in offspring production typical of marine species, (ii) fast adapting microparasites (virus, bacteria and fungi) exhibiting large variation in population sizes during epidemics, (iii) the peculiar life cycles of fungi and bacteria alternating sexual and asexual cycles and (iv) the high rates of extinction‐recolonization in spatially structured populations. We finally discuss the relevance of multiple merger models for the detection of SNPs under selection in these species, for population genomics of very large sample size and advocate to potentially examine the conclusion of previous population genetics studies.
Keywords	bacteria ; disease outbreaks ; fungi ; life history ; metagenomics ; models ; natural selection ; population size ; progeny ; prokaryotic cells ; single nucleotide polymorphism ; viruses
Language	English
Dates of publication	2014-06
Size	p. 2637-2652.
Publishing place	Blackwell Science
Document type	Article
ZDB-ID	1126687-9
ISSN	1365-294X ; 0962-1083
ISSN (online)	1365-294X
ISSN	0962-1083
DOI	10.1111/mec.12755
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Article ; Online: Ferulic Acid, Pterostilbene, and Tyrosol Protect the Heart from ER-Stress-Induced Injury by Activating SIRT1-Dependent Deacetylation of eIF2α.

Monceaux, Kévin / Gressette, Mélanie / Karoui, Ahmed / Pires Da Silva, Julie / Piquereau, Jérôme / Ventura-Clapier, Renée / Garnier, Anne / Mericskay, Mathias / Lemaire, Christophe

International journal of molecular sciences

2022 Volume 23, Issue 12

Abstract: Disturbances in Endoplasmic Reticulum (ER) homeostasis induce ER stress, which has been involved in the development and progression of various heart diseases, including arrhythmias, cardiac hypertrophy, ischemic heart diseases, dilated cardiomyopathy, ... ...

Abstract	Disturbances in Endoplasmic Reticulum (ER) homeostasis induce ER stress, which has been involved in the development and progression of various heart diseases, including arrhythmias, cardiac hypertrophy, ischemic heart diseases, dilated cardiomyopathy, and heart failure. A mild-to-moderate ER stress is considered beneficial and adaptative for heart functioning by engaging the pro-survival unfolded protein response (UPR) to restore normal ER function. By contrast, a severe or prolonged ER stress is detrimental by promoting cardiomyocyte apoptosis through hyperactivation of the UPR pathways. Previously, we have demonstrated that the NAD
MeSH term(s)	Animals ; Apoptosis ; Coumaric Acids ; Endoplasmic Reticulum Stress ; Eukaryotic Initiation Factor-2/metabolism ; Mice ; Phenylethyl Alcohol/analogs & derivatives ; Sirtuin 1/metabolism ; Stilbenes ; Unfolded Protein Response ; eIF-2 Kinase/metabolism
Chemical Substances	Coumaric Acids ; Eukaryotic Initiation Factor-2 ; Stilbenes ; 4-hydroxyphenylethanol (1AK4MU3SNX) ; pterostilbene (26R60S6A5I) ; ferulic acid (AVM951ZWST) ; eIF-2 Kinase (EC 2.7.11.1) ; Sirt1 protein, mouse (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Phenylethyl Alcohol (ML9LGA7468)
Language	English
Publishing date	2022-06-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23126628
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Article ; Online: Tebuconazole induces ROS-dependent cardiac cell toxicity by activating DNA damage and mitochondrial apoptotic pathway.

Ben Othmène, Yosra / Monceaux, Kevin / Karoui, Ahmed / Ben Salem, Intidhar / Belhadef, Anissa / Abid-Essefi, Salwa / Lemaire, Christophe

Ecotoxicology and environmental safety

2020 Volume 204, Page(s) 111040

Abstract: Tebuconazole (TEB) is a common triazole fungicide that is widely used throughout the world in agriculture applications. We previously reported that TEB induces cardiac toxicity in rats. The aim of this study was to investigate the underlying mechanism of ...

Abstract	Tebuconazole (TEB) is a common triazole fungicide that is widely used throughout the world in agriculture applications. We previously reported that TEB induces cardiac toxicity in rats. The aim of this study was to investigate the underlying mechanism of the toxicity induced by TEB in cardiac cells. TEB induced dose-dependent cell death in H9c2 cardiomyoblasts and in adult rat ventricular myocytes (ARVM). The comet assay and western blot analysis showed a concentration-dependent increase in DNA damage and in p53 and p21 protein levels 24 h after TEB treatment. Our findings also showed that TEB triggered the mitochondrial pathway of apoptosis as evidenced by a loss of mitochondrial transmembrane potential (ΔΨm), an increase in Bax/Bcl-2 ratio, an activation of caspase-9 and caspase-3, a cleavage of poly (ADP-ribose) polymerase (PARP) and an increase in the proportion of cells in the sub-G1 phase. In addition, TEB promoted ROS production in cardiac cells and consequently increased the amounts of MDA, the end product of lipid peroxidation. Treatment of cardiomyocytes with the ROS scavenger N-acetylcysteine reduced TEB-induced DNA damage and activation of the mitochondrial pathway of apoptosis. These results indicate that the genotoxic and cytotoxic effects of TEB are mediated through a ROS-dependent pathway in cardiac cells.
MeSH term(s)	Animals ; Apoptosis ; Cardiotoxicity/etiology ; Cardiotoxicity/metabolism ; DNA Damage ; Fungicides, Industrial/toxicity ; Male ; Mitochondria/drug effects ; Mitochondria/physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Triazoles/toxicity
Chemical Substances	Fungicides, Industrial ; Reactive Oxygen Species ; Triazoles ; tebuconazole (401ATW8TRW)
Language	English
Publishing date	2020-08-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	436536-7
ISSN	1090-2414 ; 0147-6513
ISSN (online)	1090-2414
ISSN	0147-6513
DOI	10.1016/j.ecoenv.2020.111040
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Book ; Online: Coalescence 2.0

Tellier, Aurelien / Lemaire, Christophe

a multiple branching of recent theoretical developments and their applications

2014

Abstract: Population genetics theory has laid the foundations for genomics analyses including the recent burst in genome scans for selection and statistical inference of past demographic events in many prokaryote, animal and plant species. Identifying SNPs under ... ...

Abstract	Population genetics theory has laid the foundations for genomics analyses including the recent burst in genome scans for selection and statistical inference of past demographic events in many prokaryote, animal and plant species. Identifying SNPs under natural selection and underpinning species adaptation relies on disentangling the respective contribution of random processes (mutation, drift, migration) from that of selection on nucleotide variability. Most theory and statistical tests have been developed using the Kingman coalescent theory based on the Wright-Fisher population model. However, these theoretical models rely on biological and life-history assumptions which may be violated in many prokaryote, fungal, animal or plant species. Recent theoretical developments of the so called multiple merger coalescent models are reviewed here ({\Lambda}-coalescent, beta-coalescent, Bolthausen-Snitzman, {\Xi}-coalescent). We explicit how these new models take into account various pervasive ecological and biological characteristics, life history traits or life cycles which were not accounted in previous theories such as 1) the skew in offspring production typical of marine species, 2) fast adapting microparasites (virus, bacteria and fungi) exhibiting large variation in population sizes during epidemics, 3) the peculiar life cycles of fungi and bacteria alternating sexual and asexual cycles, and 4) the high rates of extinction-recolonization in spatially structured populations. We finally discuss the relevance of multiple merger models for the detection of SNPs under selection in these species, for population genomics of very large sample size and advocate to potentially examine the conclusion of previous population genetics studies. Comment: 3 Figures
Keywords	Quantitative Biology - Populations and Evolution
Subject code	612
Publishing date	2014-01-21
Publishing country	us
Document type	Book ; Online
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Article ; Online: When virulence originates from non-agricultural hosts: new insights into plant breeding.

Leroy, Thibault / Le Cam, Bruno / Lemaire, Christophe

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases

2014 Volume 27, Page(s) 521–529

Abstract: Monogenic plant resistance breakdown is a model for testing evolution in action in pathogens. As a rule, plant pathologists argue that virulence - the allele that allows pathogens to overcome resistance - is due to a new mutation at the avirulence locus ... ...

Abstract	Monogenic plant resistance breakdown is a model for testing evolution in action in pathogens. As a rule, plant pathologists argue that virulence - the allele that allows pathogens to overcome resistance - is due to a new mutation at the avirulence locus within the native/endemic population that infects susceptible crops. In this article, we develop an alternative and neglected scenario where a given virulence pre-exists in a non-agricultural host and might be accidentally released or introduced on the matching resistant cultivar in the field. The main difference between the two scenarios is the divergence time expected between the avirulent and the virulent populations. As a consequence, population genetic approaches such as genome scans and Approximate Bayesian Computation methods allow explicit testing of the two scenarios by timing the divergence. This review then explores the fundamental implications of this alternative scenario for plant breeding, including the invasion of virulence or the evolution of more aggressive hybrids, and proposes concrete solutions to achieve a sustainable resistance.
MeSH term(s)	Biological Evolution ; Breeding ; Genetics, Population ; Host-Pathogen Interactions/genetics ; Models, Theoretical ; Plants/genetics ; Research ; Virulence
Language	English
Publishing date	2014-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2037068-4
ISSN	1567-7257 ; 1567-1348
ISSN (online)	1567-7257
ISSN	1567-1348
DOI	10.1016/j.meegid.2013.12.022
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Article: Hsp90 inhibition by PU-H71 induces apoptosis through endoplasmic reticulum stress and mitochondrial pathway in cancer cells and overcomes the resistance conferred by Bcl-2

Gallerne, Cindy / Prola, Alexandre / Lemaire, Christophe

Biochimica et biophysica acta. Molecular cell research. 2013 June, v. 1833, no. 6

2013

Abstract: Heat shock protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment because of its role in stabilizing the active form of a wide range of client oncoproteins. This study investigated the mechanism of apoptosis ... ...

Abstract	Heat shock protein 90 (Hsp90) has recently emerged as an attractive therapeutic target in cancer treatment because of its role in stabilizing the active form of a wide range of client oncoproteins. This study investigated the mechanism of apoptosis induced by the purine-scaffold Hsp90 inhibitor PU-H71 in different human cancer cell lines and examined the role of Bcl-2 and Bax in this process. We demonstrated that Hsp90 inhibition by PU-H71 generated endoplasmic reticulum (ER) stress and activated the Unfolded Protein Response (UPR) as evidenced by XBP1 mRNA splicing and up-regulation of Grp94, Grp78, ATF4 and CHOP. In response to PU-H71-induced ER stress, apoptosis was triggered in melanoma, cervix, colon, liver and lung cancer cells, but not in normal human fibroblasts. Apoptosis was executed through the mitochondrial pathway as shown by down-regulation of Bcl-2, up-regulation and activation of Bax, permeabilization of mitochondrial membranes, release of cytochrome c and activation of caspases. We also found that, in contrast to the ER stressor thapsigargin, PU-H71 induced apoptosis in cells overexpressing Bcl-2 and thus overcame the resistance conferred by this anti-apoptotic protein. In addition, although Bax deficiency rendered cells resistant to PU-H71, combined treatment with the anticancer drugs cisplatin or melphalan greatly sensitized these cells to PU-H71. Taken together, these data suggest that inhibition of Hsp90 by PU-H71 is a promising strategy for cancer treatment, particularly in the case of tumors resistant to conventional chemotherapy.
Keywords	apoptosis ; caspases ; cervix ; cisplatin ; colon ; cytochrome c ; drug therapy ; endoplasmic reticulum ; fibroblasts ; gene expression regulation ; heat shock proteins ; humans ; liver ; lung neoplasms ; melanoma ; messenger RNA ; mitochondrial membrane ; neoplasm cells ; oncogene proteins ; unfolded protein response
Language	English
Dates of publication	2013-06
Size	p. 1356-1366.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	283444-3
ISSN	0167-4889
ISSN	0167-4889
DOI	10.1016/j.bbamcr.2013.02.014
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