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1. Generation and characterization of CRISPR-Cas9-mediated XPC gene knockout in human skin cells

Author

Ali Nasrallah, Hamid-Reza Rezvani, Farah Kobaisi, Ahmad Hammoud, Jérôme Rambert, Jos P. H. Smits, Eric Sulpice, and Walid Rachidi

Subjects
Skin, CRISPR-Cas9, XP-C disease, DNA damage, UV irradiation, Medicine, Science
Abstract

Abstract Xeroderma pigmentosum group C (XPC) is a versatile protein crucial for sensing DNA damage in the global genome nucleotide excision repair (GG-NER) pathway. This pathway is vital for mammalian cells, acting as their essential approach for repairing DNA lesions stemming from interactions with environmental factors, such as exposure to ultraviolet (UV) radiation from the sun. Loss-of-function mutations in the XPC gene confer a photosensitive phenotype in XP-C patients, resulting in the accumulation of unrepaired UV-induced DNA damage. This remarkable increase in DNA damage tends to elevate by 10,000-fold the risk of developing melanoma and non-melanoma skin cancers. To date, creating accurate and reproducible models to study human XP-C disease has been an important challenge. To tackle this, we used CRISPR-Cas9 technology in order to knockout the XPC gene in various human skin cells (keratinocytes, fibroblasts, and melanocytes). After validation of the knockout in these edited skin cells, we showed that they recapitulate the major phenotypes of XPC mutations: photosensitivity and the impairment of UV-induced DNA damage repair. Moreover, these knockout cells demonstrated a reduced proliferative capacity compared to their respective controls. Finally, to better mimic the disease environment, we built a 3D reconstructed skin using these XPC knockout skin cells. This model exhibited an abnormal behavior, showing an extensive remodeling of its extracellular matrix compared to normal skin. Analyzing the composition of the fibroblast secretome revealed a significant augmented shift in the inflammatory response following XPC knockout. Our innovative “disease on a dish” approach can provide valuable insights into the molecular mechanisms underlying XP-C disease, paving the way to design novel preventive and therapeutic strategies to alleviate the disease phenotype. Also, given the high risk of skin cancer onset in XP-C disease, our new approach can serve as a link to draw novel insights into this elusive field.

Published
2024
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2. Synthetic rescue of Xeroderma Pigmentosum C phenotype via PIK3C3 downregulation

Author

Farah Kobaisi, Eric Sulpice, Ali Nasrallah, Patricia Obeïd, Hussein Fayyad-Kazan, Walid Rachidi, and Xavier Gidrol

Subjects
Cytology, QH573-671
Abstract

Abstract Xeroderma Pigmentosum C is a dermal hereditary disease caused by a mutation in the DNA damage recognition protein XPC that belongs to the Nucleotide excision repair pathway. XPC patients display heightened sensitivity to light and an inability to mend DNA damage caused by UV radiation, resulting in the accumulation of lesions that can transform into mutations and eventually lead to cancer. To address this issue, we conducted a screening of siRNAs targeting human kinases, given their involvement in various DNA repair pathways, aiming to restore normal cellular behavior. We introduced this siRNA library into both normal and XPC patient-derived fibroblasts, followed by UVB exposure to induce DNA damage. We assessed the reversal of the XPC phenotype by measuring reduced photosensitivity and enhanced DNA repair. Among the 1292 kinase-targeting siRNAs screened, twenty-eight showed significant improvement in cellular survival compared to cells transfected with non-targeting siRNA after UV exposure in XPC cells. From these candidates, PIK3C3 and LATS1 were identified as particularly effective, promoting over 20% repair of 6-4 photoproduct (6-4PP) DNA lesions. Specifically targeting the autophagy-related protein PIK3C3 alone demonstrated remarkable photoprotective effects in XPC-affected cells, which were validated in primary XPC patient fibroblasts and CRISPR-Cas9 engineered XPC knockout keratinocytes. PIK3C3 knock down in XP-C cells ameliorated in UVB dose response analysis, decreased apoptosis with no effect on proliferation. More importantly, PIK3C3 knock down was found to induce an increase in UVRAG expression, a previously reported cDNA conveying lower photosensitivity in XP-C cells. Thus, attempts to improve the XPC photosensitive and deficient repair phenotype using PIK3C3 inhibitors could pave a way for new therapeutic approaches delaying or preventing tumor initiation.

Published
2024
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3. Kampo herbal ointments for skin wound healing

Author

Manon Paul-Traversaz, Kaoru Umehara, Kenji Watanabe, Walid Rachidi, Michel Sève, and Florence Souard

Subjects
Kampo, ethnopharmacology, skin, wound healing, traditional medicines, herbal medicines, Therapeutics. Pharmacology, RM1-950
Abstract

The management of skin wound healing problems is a public health issue in which traditional herbal medicines could play a determining role. Kampo medicine, with three traditionally used ointments, provides interesting solutions for these dermatological issues. These ointments named Shiunkō, Chuōkō, and Shinsen taitsukō all have in common a lipophilic base of sesame oil and beeswax from which herbal crude drugs are extracted according to several possible manufacturing protocols. This review article brings together existing data on metabolites involved in the complex wound healing process. Among them are representatives of the botanical genera Angelica, Lithospermum, Curcuma, Phellodendron, Paeonia, Rheum, Rehmannia, Scrophularia, or Cinnamomum. Kampo provides numerous metabolites of interest, whose content in crude drugs is very sensitive to different biotic and abiotic factors and to the different extraction protocols used for these ointments. If Kampo medicine is known for its singular standardization, ointments are not well known, and research on these lipophilic formulas has not been developed due to the analytical difficulties encountered in biological and metabolomic analysis. Further research considering the complexities of these unique herbal ointments could contribute to a rationalization of Kampo’s therapeutic uses for wound healing.

Published
2023
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4. CRISPR-Cas9 Technology for the Creation of Biological Avatars Capable of Modeling and Treating Pathologies: From Discovery to the Latest Improvements

Author

Ali Nasrallah, Eric Sulpice, Farah Kobaisi, Xavier Gidrol, and Walid Rachidi

Subjects
CRISPR-Cas9, disease modeling, gene therapy, genome editing, Cytology, QH573-671
Abstract

This is a spectacular moment for genetics to evolve in genome editing, which encompasses the precise alteration of the cellular DNA sequences within various species. One of the most fascinating genome-editing technologies currently available is Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and its associated protein 9 (CRISPR-Cas9), which have integrated deeply into the research field within a short period due to its effectiveness. It became a standard tool utilized in a broad spectrum of biological and therapeutic applications. Furthermore, reliable disease models are required to improve the quality of healthcare. CRISPR-Cas9 has the potential to diversify our knowledge in genetics by generating cellular models, which can mimic various human diseases to better understand the disease consequences and develop new treatments. Precision in genome editing offered by CRISPR-Cas9 is now paving the way for gene therapy to expand in clinical trials to treat several genetic diseases in a wide range of species. This review article will discuss genome-editing tools: CRISPR-Cas9, Zinc Finger Nucleases (ZFNs), and Transcription Activator-Like Effector Nucleases (TALENs). It will also encompass the importance of CRISPR-Cas9 technology in generating cellular disease models for novel therapeutics, its applications in gene therapy, and challenges with novel strategies to enhance its specificity.

Published
2022
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5. Xeroderma Pigmentosum C (XPC) Mutations in Primary Fibroblasts Impair Base Excision Repair Pathway and Increase Oxidative DNA Damage

Author

Nour Fayyad, Farah Kobaisi, David Beal, Walid Mahfouf, Cécile Ged, Fanny Morice-Picard, Mohammad Fayyad-Kazan, Hussein Fayyad-Kazan, Bassam Badran, Hamid R. Rezvani, and Walid Rachidi

Subjects
Xeroderma Pigmentosum C, nucleotide excision repair, base excision repair, ultra violet (UV) light, oxidative DNA damage, oxidative stress, Genetics, QH426-470
Abstract

Xeroderma Pigmentosum C (XPC) is a multi-functional protein that is involved not only in the repair of bulky lesions, post-irradiation, via nucleotide excision repair (NER) per se but also in oxidative DNA damage mending. Since base excision repair (BER) is the primary regulator of oxidative DNA damage, we characterized, post-Ultraviolet B-rays (UVB)-irradiation, the detailed effect of three different XPC mutations in primary fibroblasts derived from XP-C patients on mRNA, protein expression and activity of different BER factors. We found that XP-C fibroblasts are characterized by downregulated expression of different BER factors including OGG1, MYH, APE1, LIG3, XRCC1, and Polβ. Such a downregulation was also observed at OGG1, MYH, and APE1 protein levels. This was accompanied with an increase in DNA oxidative lesions, as evidenced by 8-oxoguanine levels, immediately post-UVB-irradiation. Unlike in normal control cells, these oxidative lesions persisted over time in XP-C cells having lower excision repair capacities. Taken together, our results indicated that an impaired BER pathway in XP-C fibroblasts leads to longer persistence and delayed repair of oxidative DNA damage. This might explain the diverse clinical phenotypes in XP-C patients suffering from cancer in both photo-protected and photo-exposed areas. Therapeutic strategies based on reinforcement of BER pathway might therefore represent an innovative path for limiting the drawbacks of NER-based diseases, as in XP-C case.

Published
2020
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6. Impairment of Base Excision Repair in Dermal Fibroblasts Isolated From Nevoid Basal Cell Carcinoma Patients

Author

Aurélie Charazac, Nour Fayyad, David Beal, Sandrine Bourgoin-Voillard, Michel Seve, Sylvie Sauvaigo, Jérôme Lamartine, Pascal Soularue, Sandra Moratille, Michèle T. Martin, Jean-Luc Ravanat, Thierry Douki, and Walid Rachidi

Subjects
nevoid basal cell carcinoma syndrome, PTCH1 mutation, DNA repair, base excision repair, ROS production, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome is an autosomal dominant disorder whose incidence is estimated at about 1 per 55,600–256,000 individuals. It is characterized by several developmental abnormalities and an increased predisposition to the development of basal cell carcinomas (BCCs). Cutaneous fibroblasts from Gorlin patients have been shown to exhibit an increased sensitivity to ionizing radiations. Mutations in the tumor suppressor gene PTCH1, which is part of the Sonic Hedgehog (SHH) signaling pathway, are responsible for these clinical manifestations. As several genetic mutations in the DNA repair genes are responsible of photo or radiosensitivity and high predisposition to cancers, we hypothesized that these effects in Gorlin syndrome might be due to a defect in the DNA damage response (DDR) and/or the DNA repair capacities. Therefore, the objective of this work was to investigate the sensitivity of skin fibroblasts from NBCCS patients to different DNA damaging agents and to determine the ability of these agents to modulate the DNA repair capacities. Gorlin fibroblasts showed high radiosensitivity and also less resistance to oxidative stress-inducing agents when compared to control fibroblasts obtained from healthy individuals. Gorlin fibroblasts harboring PTCH1 mutations were more sensitive to the exposure to ionizing radiation and to UVA. However, no difference in cell viability was shown after exposure to UVB or bleomycin. As BER is responsible for the repair of oxidative DNA damage, we decided to assess the BER pathway efficacy in Gorlin fibroblasts. Interestingly, a concomitant decrease of both BER gene expression and BER protein activity was observed in Gorlin fibroblasts when compared to control. Our results suggest that low levels of DNA repair within Gorlin cells may lead to an accumulation of oxidative DNA damage that could participate and partly explain the radiosensitivity and the BCC-prone phenotype in Gorlin syndrome.

Published
2020
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7. Keratinocyte stem cells are more resistant to UVA radiation than their direct progeny.

Author

Elodie Metral, Nicolas Bechetoille, Frédéric Demarne, Odile Damour, and Walid Rachidi

Subjects
Medicine, Science
Abstract

The epidermis undergoes constant renewal during its lifetime. This is possible due to a special population of keratinocyte stem cells (KSCs) located at the basal layer. These cells are surrounded by their direct progeny, keratinocyte progenitors or transient amplifying cells (TAs), which arise from cell division. Skin is exposed every day to sun radiation; in particular, UVA radiation penetrates through the epidermis and induces damage to KSCs and TAs. Although keratinocytes in the basal layer are the most likely skin carcinomas and/or photoaging cells of origin, surprisingly few studies have addressed the specific responses of these cells to UV radiation. In this study, we showed for the first time that keratinocyte stem cells were more resistant to UVA irradiation than their direct progeny, transient amplifying cells. Using both the MTT assay and clonogenic assay, we found that KSCs were more photo-resistant compared to TAs after exposure to different doses of UVA (from 0 to 50 J/cm2). Moreover, KSCs had a greater ability to reconstruct human epidermis (RHE) after UVA exposure compared with TAs. Finally, investigations of DNA repair using the comet assay showed that DNA single-strand breaks and thymine dimers were repaired quicker and more efficiently in KSCs compared with TAs. In a previous work, we showed that the same stem cell population was more resistant to ionizing radiation, another carcinogenic agent. Collectively, our results combined with other observations demonstrate that keratinocyte stem cells, which are responsible for epidermal renewal throughout life, are equipped with an efficient arsenal against several genotoxic agents. Our future work will try to identify the factors or signaling pathways that are responsible for this differential photo-sensitivity and DNA repair capacity between KSCs and TAs.

Published
2018
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8. In Vitro Dermal Safety Assessment of Silver Nanowires after Acute Exposure: Tissue vs. Cell Models

Author

Sylvia G. Lehmann, Benjamin Gilbert, Thierry GG Maffeis, Alexei Grichine, Isabelle Pignot-Paintrand, Simon Clavaguera, Walid Rachidi, Michel Seve, and Laurent Charlet

Subjects
silver nanowires, cytotoxicity, skin irritation in vitro, primary keratinocytes, 3D reconstructed epidermis model, Chemistry, QD1-999
Abstract

Silver nanowires (AgNW) are attractive materials that are anticipated to be incorporated into numerous consumer products such as textiles, touchscreen display, and medical devices that could be in direct contact with skin. There are very few studies on the cellular toxicity of AgNW and no studies that have specifically evaluated the potential toxicity from dermal exposure. To address this question, we investigated the dermal toxicity after acute exposure of polymer-coated AgNW with two sizes using two models, human primary keratinocytes and human reconstructed epidermis. In keratinocytes, AgNW are rapidly and massively internalized inside cells leading to dose-dependent cytotoxicity that was not due to Ag+ release. Analysing our data with different dose metrics, we propose that the number of NW is the most appropriate dose-metric for studies of AgNW toxicity. In reconstructed epidermis, the results of a standard in vitro skin irritation assay classified AgNW as non-irritant to skin and we found no evidence of penetration into the deeper layer of the epidermis. The findings show that healthy and intact epidermis provides an effective barrier for AgNW, although the study does not address potential transport through follicles or injured skin. The combined cell and tissue model approach used here is likely to provide an important methodology for assessing the risks for skin exposure to AgNW from consumer products.

Published
2018
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14. Characterization of the epidermal-dermal junction in hiPSC-derived skin organoids

Author

Veronika Ramovs, Hans Janssen, Ignacia Fuentes, Amandine Pitaval, Walid Rachidi, Susana M. Chuva de Sousa Lopes, Christian Freund, Xavier Gidrol, Christine L. Mummery, and Karine Raymond

Subjects
EXPRESSION, Keratinocytes, VII COLLAGEN, Induced Pluripotent Stem Cells, PROTEIN, Cell Biology, Biochemistry, INTEGRINS, Organoids, FETAL SKIN, Genetics, Humans, CELL, Epidermis, Epidermolysis Bullosa, Skin, Developmental Biology
Abstract

Human induced pluripotent stem cell (hiPSC)-derived hair-bearing skin organoids offer exciting new possibilities for modeling diseases like epidermolysis bullosa (EB). These inherited diseases affect 1 in 30,000 people worldwide and result from perturbed expression and/or structure of components of the epidermal-dermal junction (EDJ). To establish whether hiPSC-derived skin organoids might be able to capture salient features of EB, it is thus important to characterize their EDJ. Here, we report successful generation of hair-bearing skin organoids from two hiPSC lines that exhibited fully stratified interfollicular epidermis. Using immunofluorescence and electron microscopy, we showed that basal keratinocytes in organoids adhere to laminin-332 and type IV collagen-rich basement membrane via type I hemidesmosomes and integrin 81-based adhesion complexes. Importantly, we demonstrated that EDJs in organoids are almost devoid of type VII collagen, a fibril that mediates anchorage of the epidermis to dermis. This should be considered when using skin organoids for EB modeling.

Published
2022

15. Effect of Ultraviolet Radiation and Benzo[a]pyrene Co-Exposure on Skin Biology: Autophagy as a Potential Target

Author

Mohammad Fayyad-Kazan, Farah Kobaisi, Ali Nasrallah, Patrick Matarrese, Richard Fitoussi, Sandrine Bourgoin-Voillard, Michel Seve, and Walid Rachidi

Subjects
Inorganic Chemistry, Organic Chemistry, skin, ultraviolet radiation, benzo[a]pyrene, proteomics, autophagy, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
Abstract

The skin is the outermost protective barrier of the human body. Its role is to protect against different physical, chemical, biological and environmental stressors. The vast majority of studies have focused on investigating the effects of single environmental stressors on skin homeostasis and the induction of several skin disorders, such as cancer or ageing. On the other hand, much fewer studies have explored the consequences of the co-exposure of skin cells to two or more stressors simultaneously, which is much more realistic. In the present study, we investigated, using mass-spectrometry-based proteomic analysis, the dysregulated biological functions in skin explants after their co-exposure to ultraviolet radiation (UV) and benzo[a]pyrene (BaP). We observed that several biological processes were dysregulated, among which autophagy appeared to be significantly downregulated. Furthermore, immunohistochemistry analysis was carried out to validate the downregulation of the autophagy process further. Altogether, the output of this study provides an insight into the biological responses of skin to combined exposure to UV + BaP and highlights autophagy as a potential target that might be considered in the future as a novel candidate for pharmacological intervention under such stress conditions.

Published
2023
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16. Isoconazole and Clemizole Hydrochloride Partially Reverse the Xeroderma Pigmentosum C Phenotype

Author

Nour Fayyad, Caroline Barette, Bassam Badran, Walid Rachidi, Mohammad Fayyad-Kazan, Xavier Gidrol, Marie-Odile Fauvarque, Farah Kobaisi, Eric Sulpice, Hussein Fayyad-Kazan, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Genetics and Chemogenomics (GenChem), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Lebanese University [Beirut] (LU), and ANR-18-CE17-0017,PGI2Heal,La voie de la PGI2 pour améliorer la cicatrisation des plaies du pied diabétique(2018)

Subjects
0301 basic medicine, Xeroderma pigmentosum, Miconazole, QH301-705.5, DNA damage, DNA repair, Cell Survival, Ultraviolet Rays, [SDV]Life Sciences [q-bio], XPC, Pyrimidine dimer, Skin Diseases, Catalysis, Article, Cell Line, Inorganic Chemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Isoconazole, chemical screen, medicine, Humans, Pyrimidone, Biology (General), Physical and Theoretical Chemistry, QD1-999, Molecular Biology, Spectroscopy, Xeroderma Pigmentosum, skin cancer, Organic Chemistry, Drug Repositioning, General Medicine, medicine.disease, Computer Science Applications, Clemizole, UV, Chemistry, 030104 developmental biology, chemistry, Apoptosis, 030220 oncology & carcinogenesis, Cancer research, Benzimidazoles
Abstract

Xeroderma Pigmentosum protein C (XPC) is involved in recognition and repair of bulky DNA damage such as lesions induced by Ultra Violet (UV) radiation. XPC-mutated cells are, therefore, photosensitive and accumulate DNA damage leading to increased cancer incidence. Here, we performed a high-throughput screen to identify chemicals capable of normalizing the XP-C phenotype (hyper-photosensitivity and accumulation of photoproducts). Fibroblasts from XP-C patients were treated with a library of approved chemical drugs. Out of 1280 tested chemicals, 16 showed ≥ 25% photo-resistance with RZscore above 2.6 and two drugs were able to favor repair of 6 − 4 pyrimidine pyrimidone photoproducts (6-4PP). Among these two compounds, Isoconazole could partially inhibit apoptosis of the irradiated cells especially when cells were post-treated directly after UV irradiation while Clemizole Hydrochloride-mediated increase in viability was dependent on both pre and post-treatment. No synergistic effect was recorded following combined drug treatment and the compounds exerted no effect on the proliferative capacity of the cells post UV exposure. Amelioration of XP-C phenotype is a pave way towards understanding the accelerated skin cancer initiation in XP-C patients. Further examination is required to decipher the molecular mechanisms targeted by these two chemicals.

Published
2021
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19. Xeroderma Pigmentosum C: A Valuable Tool to Decipher the Signaling Pathways in Skin Cancers

Author

Bassam Badran, Michel Seve, Walid Rachidi, Mohammad Fayyad-Kazan, Farah Kobaisi, Hussein Fayyad-Kazan, Nour Fayyad, and A. Nasrallah

Subjects
0301 basic medicine, Proteomics, Aging, Xeroderma pigmentosum, Skin Neoplasms, DNA Repair, Proteome, Ultraviolet Rays, Mutant, Review Article, Gene mutation, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, medicine, Biomarkers, Tumor, Missense mutation, Animals, Humans, Xeroderma Pigmentosum, QH573-671, Incidence, Genodermatosis, Cancer, Cell Biology, General Medicine, medicine.disease, 3. Good health, 030104 developmental biology, Codon, Nonsense, 030220 oncology & carcinogenesis, Cancer research, Skin cancer, Cytology, Nucleotide excision repair, DNA Damage, Signal Transduction
Abstract

Xeroderma pigmentosum (XP) is a rare autosomal genodermatosis that manifests clinically with pronounced sensitivity to ultraviolet (UV) radiation and the high probability of the occurrence of different skin cancer types in XP patients. XP is mainly caused by mutations in XP-genes that are involved in the nucleotide excision repair (NER) pathway that functions in the removal of bulky DNA adducts. Besides, the aggregation of DNA lesions is a life-threatening event that might be a key for developing various mutations facilitating cancer appearance. One of the key players of NER is XPC that senses helical distortions found in damaged DNA. The majority of XPC gene mutations are nonsense, and some are missense leading either to the loss of XPC protein or to the expression of a truncated nonfunctional version. Given that no cure is yet available, XPC patients should be completely protected and isolated from all types of UV radiations (UVR). Although it is still poorly understood, the characterization of the proteomic signature of an XPC mutant is essential to identify mediators that could be targeted to prevent cancer development in XPC patients. Unraveling this proteomic signature is fundamental to decipher the signaling pathways affected by the loss of XPC expression following exposure to UVB radiation. In this review, we will focus on the signaling pathways disrupted in skin cancer, pathways modulating NER’s function, including XPC, to disclose signaling pathways associated with XPC loss and skin cancer occurrence.

Published
2021

20. Age-Dependent Protective Effect of Selenium against UVA Irradiation in Primary Human Keratinocytes and the Associated DNA Repair Signature

Author

Anne-Marie Roussel, Walid Rachidi, E. Blouin, C. Favrot, M. T. Leccia, David Béal, Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département de dermatologie, allergologie et photobiologie [Hôpital Michallon du CHU Grenoble Alpes], Centre Hospitalier Universitaire [Grenoble] (CHU)-Hôpital Michallon, Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
Adult, Keratinocytes, 0301 basic medicine, Aging, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Article Subject, DNA Repair, Ultraviolet Rays, DNA repair, Photoaging, chemistry.chemical_element, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Skin Aging, Selenium, Young Adult, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Humans, Uva irradiation, lcsh:QH573-671, Young adult, Cytotoxicity, Cells, Cultured, Aged, integumentary system, lcsh:Cytology, business.industry, Age Factors, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, General Medicine, Middle Aged, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cancer research, Keratinocyte, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Research Article
Abstract

International audience; Few studies have focused on the protective role of selenium (Se) against skin aging and photoaging even though selenoproteins are essential for keratinocyte function and skin development. To the best of our knowledge, the impact of Se supplementation on skin cells from elderly and young donors has not been reported. Therefore, the main objective of our study was to evaluate the effects of Se supplementation on skin keratinocytes at baseline and after exposure to ultraviolet A (UVA) irradiation. Low doses of Se (30 nM) were very potently protective against UVA-induced cytotoxicity in young keratinocytes, whereas the protection efficiency of Se in old keratinocytes required higher concentrations (240 nM). Additionally, the DNA repair ability of the old keratinocytes drastically decreased compared with that of the young keratinocytes at baseline and after the UVA exposure. The Se supplementation significantly enhanced the DNA repair of 8-oxoguanine (8oxoG) only in the keratinocytes isolated from young donors. Therefore, aged keratinocytes have an increased vulnerability to oxidative DNA damage, and the Se needs in the elderly should be considered. Strengthening DNA repair activities with Se supplementation may represent a new strategy to combat aging and skin photoaging.

Published
2018
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21. Gadolinium-based nanoparticles can overcome the radioresistance of head and neck squamous cell carcinoma through the induction of autophagy

Author

S. Gerbaud, Stéphanie Simonet, Dominique Ardail, O. Tillement, C. Malesys, David Béal, Walid Rachidi, F. Lux, Hussein Fayyad-Kazan, Claire Rodriguez-Lafrasse, Institut de Physique des 2 Infinis de Lyon (IP2I Lyon), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Unité Médicale d'Oncologie Moléculaire et Transfert (UMOMT), Hospices Civils de Lyon (HCL), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Biomicrotechnologie et génomique fonctionnelle (BIOMICS ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Formation, élaboration de nanomatériaux et cristaux (FENNEC), Institut Lumière Matière [Villeurbanne] (ILM), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Laboratory of Cancer Biology and Molecular Immunology, ANR-11-LABX-0063,PRIMES,Physique, Radiobiologie, Imagerie Médicale et Simulation(2011), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Genetics and Chemogenomics (GenChem), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
Programmed cell death, DNA damage, medicine.medical_treatment, 0206 medical engineering, Cell, Biomedical Engineering, Pharmaceutical Science, Medicine (miscellaneous), Metal Nanoparticles, Bioengineering, Apoptosis, Gadolinium, 02 engineering and technology, Cell Line, [SPI]Engineering Sciences [physics], Radioresistance, Cell Line, Tumor, medicine, Autophagy, Humans, [CHIM]Chemical Sciences, General Materials Science, [PHYS]Physics [physics], Tumor, business.industry, Squamous Cell Carcinoma of Head and Neck, Carcinoma, 021001 nanoscience & nanotechnology, medicine.disease, 020601 biomedical engineering, Head and neck squamous-cell carcinoma, 3. Good health, Radiation therapy, medicine.anatomical_structure, Squamous Cell, Head and Neck Neoplasms, Cancer research, Carcinoma, Squamous Cell, 0210 nano-technology, business
Abstract

Radiation therapy is a mainstay in the therapeutic management of Head and Neck Squamous Cell Carcinoma (HNSCC). Despite significant progress in this field, radioresistance still accounts for most treatment failures. Gadolinium-based nanoparticles (GBNs) have shown great promises as radiosensitizers but the underlying sensitizing mechanism is still largely unknown with regards to the disparities obtained in in vitro studies. In this study, we show that a new formulation of GBNs, AGuIX®, can radiosensitize HNSCC after cell uptake and further accumulation in lysosomes. Although radiation alone triggered late apoptosis and mitochondrial impairment, the pre-treatment with GBNs led to complex DNA damage and a specific increase of autophagic cell death. In addition, a significant radio-enhancement effect was obtained after the pre-conditioning of cells with a glutathione inhibitor before GBNs treatment and radiation exposure. Overall, our results provide additional information on the radio-enhancing properties of GBNs in the management of radioresistant HNSCC.

Published
2020
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23. The effects of different bisphenol derivatives on oxidative stress, DNA damage and DNA repair in RWPE-1 cells: A comparative study

Author

Belma Koçer Gümüşel, Özge Köse, David Béal, Pinar Erkekoglu, Walid Rachidi, and Hussein Fayyad-Kazan

Subjects
Male, endocrine system, DNA Repair, DNA repair, Bisphenol, DNA damage, Glutathione reductase, 010501 environmental sciences, Endocrine Disruptors, Toxicology, medicine.disease_cause, 01 natural sciences, Risk Assessment, Antioxidants, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Phenols, medicine, Humans, Sulfones, Benzhydryl Compounds, 030304 developmental biology, 0105 earth and related environmental sciences, chemistry.chemical_classification, 0303 health sciences, urogenital system, Glutathione peroxidase, Prostate, Epithelial Cells, Comet assay, Oxidative Stress, Biochemistry, Bisphenol S, chemistry, Gene Expression Regulation, Comet Assay, hormones, hormone substitutes, and hormone antagonists, Genotoxicity, DNA Damage
Abstract

Bisphenol A (BPA) is a well-known endocrine disruptor and it is widely used mainly in the plastics industry. Due to recent reports on its possible impact on health (particularly on the male reproductive system), bisphenol F (BPF) and bisphenol S (BPS) are now being used as alternatives. In this study, RWPE-1 cells were used as a model to compare cytotoxicity, oxidative stress-causing potential and genotoxicity of these chemicals. In addition, the effects of the bisphenol derivatives were assessed on DNA repair proteins. RWPE-1 cells were incubated with BPA, BPF, and BPS at concentrations of 0-600 μM for 24 h. The inhibitory concentration 20 (IC20 , concentration that causes 20% of cell viability loss) values for BPA, BPF, and BPS were 45, 65, and 108 μM, respectively. These results indicated that cytotoxicity potentials were ranked as BPA > BPF > BPS. We also found alterations in superoxide dismutase, glutathione peroxidase and glutathione reductase activities, and glutathione and total antioxidant capacity in all bisphenol-exposed groups. In the standard and modified Comet assay, BPS produced significantly higher levels of DNA damage vs the control. DNA repair proteins (OGG1, Ape-1, and MyH) involved in the base excision repair pathway, as well as p53 protein levels were down-regulated in all of the bisphenol-exposed groups. We found that the BPA alternatives were also cytotoxic and genotoxic, and changed the expressions of DNA repair enzymes. Therefore, further studies are needed to assess whether they can be used safely as alternatives to BPA or not.

Published
2019

24. High-throughput synthetic rescue for exhaustive characterization of suppressor mutations in human genes

Author

Farah, Kobaisi, Nour, Fayyad, Eric, Sulpice, Bassam, Badran, Hussein, Fayyad-Kazan, Walid, Rachidi, and Xavier, Gidrol

Subjects
Cell phenotype, Suppressor mutation, Review, Gene Knockout Techniques, Suppression, Genetic, Mutagenesis, Gene Knockdown Techniques, Neoplasms, Genetic screening, Animals, Humans, RNA Interference, CRISPR-Cas Systems, Synthetic rescue
Abstract

Inherited or acquired mutations can lead to pathological outcomes. However, in a process defined as synthetic rescue, phenotypic outcome created by primary mutation is alleviated by suppressor mutations. An exhaustive characterization of these mutations in humans is extremely valuable to better comprehend why patients carrying the same detrimental mutation exhibit different pathological outcomes or different responses to treatment. Here, we first review all known suppressor mutations’ mechanisms characterized by genetic screens on model species like yeast or flies. However, human suppressor mutations are scarce, despite some being discovered based on orthologue genes. Because of recent advances in high-throughput screening, developing an inventory of human suppressor mutations for pathological processes seems achievable. In addition, we review several screening methods for suppressor mutations in cultured human cells through knock-out, knock-down or random mutagenesis screens on large scale. We provide examples of studies published over the past years that opened new therapeutic avenues, particularly in oncology.

Published
2019

27. Signaling Pathways, Chemical and Biological Modulators of Nucleotide Excision Repair: The Faithful Shield against UV Genotoxicity

Author

B. Badran, Xavier Gidrol, H. Fayyad-Kazan, Hamid Reza Rezvani, Nour Fayyad, Farah Kobaisi, Walid Rachidi, Eric Sulpice, M. Fayyad-Kazan, Biomicrotechnologie et génomique fonctionnelle (BIOMICS), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and ANR-18-CE17-0017,PGI2Heal,La voie de la PGI2 pour améliorer la cicatrisation des plaies du pied diabétique(2018)

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Aging, Xeroderma pigmentosum, DNA Repair, Ultraviolet Rays, DNA repair, DNA damage, [SDV]Life Sciences [q-bio], Trichothiodystrophy, Review Article, Genotoxic Stress, Biology, Biochemistry, Cockayne syndrome, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Trichothiodystrophy Syndromes, lcsh:QH573-671, Cockayne Syndrome, skin and connective tissue diseases, PI3K/AKT/mTOR pathway, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Xeroderma Pigmentosum, 0303 health sciences, lcsh:Cytology, nutritional and metabolic diseases, Cell Biology, General Medicine, medicine.disease, 3. Good health, enzymes and coenzymes (carbohydrates), 030220 oncology & carcinogenesis, biological sciences, Cancer research, DNA Damage, Signal Transduction, Nucleotide excision repair
Abstract

The continuous exposure of the human body’s cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several effective repair mechanisms, among which is nucleotide excision repair (NER), to counteract these lesions. NER includes both global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Deficiencies in the NER pathway underlie the development of several DNA repair diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Deficiencies in GG-NER and TC-NER render individuals to become prone to cancer and neurological disorders, respectively. Therefore, NER regulation is of interest in fine-tuning these risks. Distinct signaling cascades including the NFE2L2 (NRF2), AHR, PI3K/AKT1, MAPK, and CSNK2A1 pathways can modulate NER function. In addition, several chemical and biological compounds have proven success in regulating NER’s activity. These modulators, particularly the positive ones, could therefore provide potential treatments for genetic DNA repair-based diseases. Negative modulators, nonetheless, can help sensitize cells to killing by genotoxic chemicals. In this review, we will summarize and discuss the major upstream signaling pathways and molecules that could modulate the NER’s activity.

Published
2019
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28. Investigating the toxic effects induced by iron oxide nanoparticles on neuroblastoma cell line: an integrative study combining cytotoxic, genotoxic and proteomic tools

Author

Mohsen Sakly, David Béal, Sylvie Berthier, Michel Seve, Dalel Askri, Walid Rachidi, Benoit Chovelon, Salem Amara, Sylvia G. Lehmann, Valérie Cunin, Josiane Arnaud, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Enzymologie (DBPC), CHU Grenoble-GREPI EA 2938, Département de pharmacochimie moléculaire (DPM ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de biologie intégrée, CHU Grenoble-Hôpital Michallon, Laboratoire de Physiologie Intégrée, Faculté des Sciences de Bizerte [Université de Carthage], Université de Carthage - University of Carthage-Université de Carthage - University of Carthage, Physiologie Intégrée, Centre Hospitalier Universitaire [Grenoble] (CHU), PROteomics and METabolomics Platform [Grenoble] (PROMETHEE), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Proteomics, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Proteome, Cell Survival, Cell, Biomedical Engineering, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 010501 environmental sciences, Toxicology, Ferric Compounds, 01 natural sciences, Iron oxide nanoparticles neuroblastoma toxicity proteomics, chemistry.chemical_compound, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Animals, Humans, Cytotoxic T cell, Particle Size, 0105 earth and related environmental sciences, Membrane Potential, Mitochondrial, Chemistry, Cell Cycle, Cell Membrane, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell cycle, 021001 nanoscience & nanotechnology, 3. Good health, Cell biology, Comet assay, medicine.anatomical_structure, Toxicity, Cancer cell, Nanoparticles, Comet Assay, Reactive Oxygen Species, 0210 nano-technology, Iron oxide nanoparticles, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, DNA Damage
Abstract

International audience; Nanomaterials have gained much attention for their use and benefit in several fields. Iron Oxide Nanoparticles (IONPs) have been used in Biomedicine as contrast agents for imaging cancer cells. However, several studies reported the potential toxicity of those nanoparticles in different models, especially in cells. Therefore, in our present study, we investigated the effects of IONPs on the SH-SY5Y neuroblastoma cell line. We carried out cytotoxic and genotoxic studies to evaluate the phenotypic effects, and proteomic investigation to evaluate the molecular effects and the mechanisms by which this kind of NPs could induce toxicity. Our results showed that the use of three different sizes of IONPs (14, 22 and 30 nm) induced cell detachment, cell morphological changes, size, and concentration-dependent IONP internalization and cell mortality. IONPs induced slight genotoxic damage assayed by modified comet assay without affecting cell cycle, mitochondrial function, membrane integrity, intracellular calcium level, and without inducing ROS generation. All the studies were performed to compare also the effects of IONPs to the ferric iron by incubating cells with equivalent concentration of FeCl3. In all tests, the NPs exhibited more toxicity than the ferric iron. The proteomic analysis followed by gene ontology and pathway analysis evidenced the effects of IONPs on cytoskeleton, cell apoptosis, and cancer development. Our findings provided more information about IONP effects on human cells and especially on cancer cell line.

Published
2019
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29. The Polyphenol-Rich Extract from

Author

Elodie, Clain, Juliano G, Haddad, Andrea C, Koishi, Laura, Sinigaglia, Walid, Rachidi, Philippe, Desprès, Claudia N, Duarte Dos Santos, Pascale, Guiraud, Nolwenn, Jouvenet, and Chaker, El Kalamouni

Subjects
nutraceuticals, Plants, Medicinal, Psiloxylon mauritianum, Plant Extracts, Zika Virus Infection, viruses, Polyphenols, Zika Virus, Dengue Virus, Antiviral Agents, Article, Dengue, Magnoliopsida, Chlorocebus aethiops, antiviral activity, natural compounds, Animals, Humans, Reunion, Vero Cells, Cells, Cultured
Abstract

The recent emergence and re-emergence of viral infections transmitted by vectors, such as the Zika virus (ZIKV) and Dengue virus (DENV), is a cause for international concern. These highly pathogenic arboviruses represent a serious health burden in tropical and subtropical areas of the world. Despite the high morbidity and mortality associated with these viral infections, antiviral therapies are missing. Medicinal plants have been widely used to treat various infectious diseases since millenaries. Several compounds extracted from plants exhibit potent effects against viruses in vitro, calling for further investigations regarding their efficacy as antiviral drugs. Here, we demonstrate that an extract from Psiloxylon mauritianum, an endemic medicinal plant from Reunion Island, inhibits the infection of ZIKV in vitro without exhibiting cytotoxic effects. The extract was active against different ZIKV African and Asian strains, including an epidemic one. Time-of-drug-addition assays revealed that the P. mauritianum extract interfered with the attachment of the viral particles to the host cells. Importantly, the P. mauritianum extract was also able to prevent the infection of human cells by four dengue virus serotypes. Due to its potency and ability to target ZIKV and DENV particles, P. mauritianum may be of value for identifying and characterizing antiviral compounds to fight medically-important flaviviruses.

Published
2019

30. Keratinocyte stem cells are more resistant to UVA radiation than their direct progeny

Author

Nicolas Bechetoille, Frédéric Demarne, Walid Rachidi, Elodie Metral, Odile Damour, Banque de Tissus et de Cellules, Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
Adult, Keratinocytes, 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, DNA Repair, Cell division, Ultraviolet Rays, Photoaging, Primary Cell Culture, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Radiation Tolerance, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Humans, DNA Breaks, Single-Stranded, Progenitor cell, Clonogenic assay, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Skin, Multidisciplinary, Epidermis (botany), Chemistry, Stem Cells, lcsh:R, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Dermis, medicine.disease, Cell biology, Comet assay, 030104 developmental biology, medicine.anatomical_structure, Epidermal Cells, Pyrimidine Dimers, Female, lcsh:Q, Comet Assay, Epidermis, Stem cell, Keratinocyte, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, DNA Damage
Abstract

The epidermis undergoes constant renewal during its lifetime. This is possible due to a special population of keratinocyte stem cells (KSCs) located at the basal layer. These cells are surrounded by their direct progeny, keratinocyte progenitors or transient amplifying cells (TAs), which arise from cell division. Skin is exposed every day to sun radiation; in particular, UVA radiation penetrates through the epidermis and induces damage to KSCs and TAs. Although keratinocytes in the basal layer are the most likely skin carcinomas and/or photoaging cells of origin, surprisingly few studies have addressed the specific responses of these cells to UV radiation. In this study, we showed for the first time that keratinocyte stem cells were more resistant to UVA irradiation than their direct progeny, transient amplifying cells. Using both the MTT assay and clonogenic assay, we found that KSCs were more photo-resistant compared to TAs after exposure to different doses of UVA (from 0 to 50 J/cm2). Moreover, KSCs had a greater ability to reconstruct human epidermis (RHE) after UVA exposure compared with TAs. Finally, investigations of DNA repair using the comet assay showed that DNA single-strand breaks and thymine dimers were repaired quicker and more efficiently in KSCs compared with TAs. In a previous work, we showed that the same stem cell population was more resistant to ionizing radiation, another carcinogenic agent. Collectively, our results combined with other observations demonstrate that keratinocyte stem cells, which are responsible for epidermal renewal throughout life, are equipped with an efficient arsenal against several genotoxic agents. Our future work will try to identify the factors or signaling pathways that are responsible for this differential photo-sensitivity and DNA repair capacity between KSCs and TAs.

Published
2018

31. Human CD8

Author

Redouane, Rouas, Makram, Merimi, Mehdi, Najar, Nabil, El Zein, Mohammad, Fayyad-Kazan, Mimoune, Berehab, Douaa, Agha, Dominique, Bron, Arsene, Burny, Walid, Rachidi, Bassam, Badran, Philippe, Lewalle, and Hussein, Fayyad-Kazan

Subjects
MicroRNAs, Gene Expression Regulation, Transforming Growth Factor beta, Gene Expression Profiling, Gene Expression, Humans, Forkhead Transcription Factors, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Interleukin-10
Abstract

Regulatory T cells (Tregs) are central for maintaining immune balance and their dysfunction drives the expansion of critical immunologic disorders. During the past decade, microRNAs (miRNAs) have emerged as potent regulators of gene expression among which immune-related genes and their immunomodulatory properties have been associated with different immune-based diseases. The miRNA signature of human peripheral blood (PB) CD8

Published
2017

32. Selenium preserves keratinocyte stemness and delays senescence by maintaining epidermal adhesion

Author

David Béal, Eric Blouin, Anne-Marie Roussel, Lara Jobeili, Walid Rachidi, Patricia Rousselle, Odile Damour, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Environnement Ville Société (EVS), École normale supérieure - Lyon (ENS Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Environnement, Ville, Société (EVS), École normale supérieure de Lyon (ENS de Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Labcatal Pharmaceuticals, ANR [ANR-13-RPIB-0003-01], Biologie et physiopathologie cutanées : expression génique, signalisation et thérapie, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Banque de Tissus et de Cellules, Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Keratinocytes, Aging, Antioxidant, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Time Factors, medicine.medical_treatment, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Antioxidants, Basement Membrane, Skin Aging, 0302 clinical medicine, complémentation, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], selenium, Geriatry and gerontology, Cells, Cultured, Cellular Senescence, ComputingMilieux_MISCELLANEOUS, kératinocyte, integumentary system, Stem Cells, food and beverages, Cell Differentiation, Environmental exposure, vieillissement, 3. Good health, Cell biology, adhesion, medicine.anatomical_structure, Phenotype, replicative life span, skin aging, keratinocytes stem cells, Keratinocyte, Research Paper, Senescence, Cell Survival, chemistry.chemical_element, sénescence, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Sodium Selenite, antioxydant, adhésion cellulaire, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Cell Adhesion, Skin equivalent, Humans, Cell Proliferation, différenciation cellulaire, Dose-Response Relationship, Drug, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, 030104 developmental biology, chemistry, peau, Gériatrie et gérontologie, Skin cancer, Epidermis, 030217 neurology & neurosurgery, Selenium, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; Skin is constantly exposed to environmental factors such as pollutants, chemicals and ultra violet radiation (UV), which can induce premature skin aging and increase the risk of skin cancer. One strategy to reduce the effect of oxidative stress produced by environmental exposure is the application of antioxidant molecules. Among the endogenous antioxidants, selenoproteins play a key role in antioxidant defense and in maintaining a reduced cellular environment. Selenium, essential for the activity of selenoproteins, is a trace element that is not synthesized by organisms and must be supplied by diet or supplementation. The aim of this study is to evaluate the effect of Selenium supplementation on skin aging, especially on keratinocytes, the main cells of the epidermis. Our results demonstrate for the first time to our knowledge, the major role of Selenium on the replicative life span of keratinocytes and on aging skin. Selenium protects keratinocyte stem cells (KSCs) against senescence via preservation of their stemness phenotype through adhesion to the basement membrane. Additionally, Selenium supplementation maintains the homeostasis of skin during chronological aging in our senescent skin equivalent model. Controlled supplementation with Selenium could be a new strategy to protect skin against aging.

Published
2017
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33. Long-term Genoprotection Effect of Sechium edule Fruit Extract Against UVA Irradiation in Keratinocytes

Author

Nicolas Bechetoille, Elodie Metral, Odile Damour, Frédéric Demarne, and Walid Rachidi

Subjects
0301 basic medicine, Keratinocytes, Antioxidant, DNA Repair, DNA repair, DNA damage, Cell Survival, Ultraviolet Rays, medicine.medical_treatment, Photoaging, Primary Cell Culture, Radiation-Protective Agents, Biology, Biochemistry, Antioxidants, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Radiation Protection, medicine, Humans, Physical and Theoretical Chemistry, Cytotoxicity, Plant Extracts, General Medicine, medicine.disease, Thymine, Skin Aging, Cucurbitaceae, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Photoprotection, sense organs, DNA, DNA Damage
Abstract

Photoprotection is essential to prevent the long-term deleterious effects of ultraviolet (UV), including skin cancer and photoaging. So far, there has been an increase in the use of natural bioactive phytochemicals for the development of more effective skin photoprotective agents. However, the molecular mechanisms underlying the photochemoprotection activity of such compounds remain largely unknown. The objective of this study was to investigate the effects of a Sechium edule fruit extract (SEE) in terms of photoprotection against UVA in primary human keratinocytes. We found that SEE protected keratinocytes against UVA-induced cytotoxicity, decreased the intracellular amounts of ROS and reduced oxidatively induced DNA lesions after UVA exposure. Furthermore, SEE decreased the induction of CPD lesions in UVA-irradiated keratinocytes and exhibited increased DNA repair of such photoproducts at 24 h post-exposure. Finally, using DNA repair biochips, we demonstrated that SEE-treated keratinocytes had DNA enzymatic repair activities more efficient for abasic sites, CPD and thymine glycols. Therefore, the benefits of SEE against UVA could be explained by a combination of antioxidant activity, the reduction in DNA damage and the enhancement of DNA repair capacities. This article is protected by copyright. All rights reserved.

Published
2017

34. Effects of Iron Oxide Nanoparticles (γ-Fe2O3) on Liver, Lung and Brain Proteomes following Sub-Acute Intranasal Exposure: A New Toxicological Assessment in Rat Model Using iTRAQ-Based Quantitative Proteomics

Author

David Béal, Souhir Ouni, Mohsen Sakly, Michel Seve, Dalel Askri, Walid Rachidi, Valérie Cunin, Sylvia G. Lehmann, and Salem Amara

Subjects
Male, 0301 basic medicine, Proteome, Quantitative proteomics, Metal Nanoparticles, Stimulation, 02 engineering and technology, Pharmacology, Proteomics, medicine.disease_cause, Ferric Compounds, Article, Catalysis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, proteomics, Immune system, In vivo, Toxicity Tests, medicine, Animals, rat, Physical and Theoretical Chemistry, Lung, lcsh:QH301-705.5, Molecular Biology, Spectroscopy, Chemistry, Organic Chemistry, iron oxide nanoparticles, Brain, toxicity, General Medicine, 021001 nanoscience & nanotechnology, Rats, Computer Science Applications, in vivo, 030104 developmental biology, Liver, lcsh:Biology (General), lcsh:QD1-999, Toxicity, 0210 nano-technology, Biomarkers, Oxidative stress, Signal Transduction
Abstract

Iron Oxide Nanoparticles (IONPs) present unique properties making them one of the most used NPs in the biomedical field. Nevertheless, for many years, growing production and use of IONPs are associated with risks that can affect human and the environment. Thus, it is essential to study the effects of these nanoparticles to better understand their mechanism of action and the molecular perturbations induced in the organism. In the present study, we investigated the toxicological effects of IONPs (&gamma, Fe2O3) on liver, lung and brain proteomes in Wistar rats. Exposed rats received IONP solution during 7 consecutive days by intranasal instillation at a dose of 10 mg/kg body weight. An iTRAQ-based quantitative proteomics was used to study proteomic variations at the level of the three organs. Using this proteomic approach, we identified 1565, 1135 and 1161 proteins respectively in the brain, liver and lung. Amon them, we quantified 1541, 1125 and 1128 proteins respectively in the brain, liver and lung. Several proteins were dysregulated comparing treated samples to controls, particularly, proteins involved in cytoskeleton remodeling, cellular metabolism, immune system stimulation, inflammation process, response to oxidative stress, angiogenesis, and neurodegenerative diseases.

Published
2019
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37. The effects of selenium and the GPx-1 selenoprotein on the phosphorylation of H2AX

Author

Anita Jerome-Morais, Alan M. Diamond, Walid Rachidi, P.H. Gann, and Soumen Bera

Subjects
inorganic chemicals, DNA Repair, DNA repair, DNA damage, Biophysics, chemistry.chemical_element, Protein Serine-Threonine Kinases, Biology, environment and public health, Biochemistry, Article, Histones, Bleomycin, Selenium, Glutathione Peroxidase GPX1, Cell Line, Tumor, Radiation, Ionizing, Humans, CHEK1, Viability assay, Phosphorylation, Selenoproteins, Molecular Biology, chemistry.chemical_classification, Glutathione Peroxidase, Antibiotics, Antineoplastic, Glutathione peroxidase, Molecular biology, Checkpoint Kinase 2, enzymes and coenzymes (carbohydrates), chemistry, Checkpoint Kinase 1, Selenoprotein, Protein Kinases, DNA Damage
Abstract

Background Significant data supports the health benefits of selenium although supplementation trials have yielded mixed results. GPx-1, whose levels are responsive to selenium availability, is implicated in cancer etiology by human genetic data. Selenium's ability to alter the phosphorylation of the H2AX, a histone protein that functions in the reduction of DNA damage by recruiting repair proteins to the damage site, following exposure to ionizing radiation and bleomycin was investigated. Methods Human cell lines that were either exposed to selenium or were transfected with a GPx-1 expression construct were exposed to ionizing radiation or bleomycin. Phosphorylation of histone H2AX was quantified by flow cytometry and survival by the MTT assay. Phosphorylation of the Chk1 and Chk2 checkpoint proteins was quantified by western blotting. Results In colon-derived cells, selenium increases GPx-1 and attenuated H2AX phosphorylation following genotoxic exposures while the viability of these cells was unaffected. MCF-7 cells and transfectants that express high GPx-1 levels were exposed to ionizing radiation and bleomycin, and H2AX phosphorylation and cell viability were assessed. GPx-1 increased H2AX phosphorylation and viability following the induction of DNA damage while enhancing the levels of activated Chk1 and Chk2. Conclusions Exposure of mammalian cells to selenium can alter the DNA damage response and do so by mechanisms that are dependent and independent of its effect on GPx-1. General significance Selenium and GPx-1 may stimulate the repair of genotoxic DNA damage and this may account for some of the benefits attributed to selenium intake and elevated GPx-1 activity.

Published
2013
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38. Tubulin Beta-3 Chain as a New Candidate Protein Biomarker of Human Skin Aging: A Preliminary Study

Author

Michel Seve, Sylvia G. Lehmann, Walid Rachidi, Sandrine Bourgoin-Voillard, Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU), PROteomics and METabolomics Platform [Grenoble] (PROMETHEE), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
0301 basic medicine, Male, Aging, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Article Subject, Human skin, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Skin Aging, 03 medical and health sciences, 0302 clinical medicine, Western blot, Tubulin, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Humans, lcsh:QH573-671, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, biology, medicine.diagnostic_test, integumentary system, lcsh:Cytology, Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, General Medicine, Cell cycle, Molecular biology, 3. Good health, Cell biology, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Biomarker (medicine), Female, Signal transduction, Biomarkers, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Research Article
Abstract

International audience; Skin aging is a complex process, and a lot of efforts have been made to identify new and specific targets that could help to diagnose, prevent, and treat skin aging. Several studies concerning skin aging have analyzed the changes in gene expression, and very few investigations have been performed at the protein level. Moreover, none of these proteomic studies has used a global quantitative labeled proteomic offgel approach that allows a more accurate description of aging phenotype. We applied such an approach on human primary keratinocytes obtained from sun-nonexposed skin biopsies of young and elderly women. A total of 517 unique proteins were identified, and 58 proteins were significantly differentially expressed with 40 that were downregulated and 18 upregulated with aging. Gene ontology and pathway analysis performed on these 58 putative biomarkers of skin aging evidenced that these dysregulated proteins were mostly involved in metabolism and cellular processes such as cell cycle and signaling pathways. Change of expression of tubulin beta-3 chain was confirmed by western blot on samples originated from several donors. Thus, this study suggested the tubulin beta-3 chain has a promising biomarker in skin aging.

Published
2017
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39. Alzheimer’s Disease-Associated Neurotoxic Peptide Amyloid-Β Impairs Base Excision Repair in Human Neuroblastoma Cells

Author

Anne Forestier, Thierry Douki, Sylvie Sauvaigo, Viviana De Rosa, Christine Demeilliers, and Walid Rachidi

Subjects
s disease, lcsh:Chemistry, Alzheimer&#8217, lcsh:Biology (General), lcsh:QD1-999, neurodegenerative disorders, DNA damage, DNA repair, Base Excision Repair, oxidative stress, 8oxoGuanine, OGG1, lcsh:QH301-705.5
Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in developed countries. It is characterized by two major pathological hallmarks, one of which is the extracellular aggregation of the neurotoxic peptide amyloid-β (Aβ), which is known to generate oxidative stress. In this study, we showed that the presence of Aβ in a neuroblastoma cell line led to an increase in both nuclear and mitochondrial DNA damage. Unexpectedly, a concomitant decrease in basal level of base excision repair, a major route for repairing oxidative DNA damage, was observed at the levels of both gene expression and protein activity. Moreover, the addition of copper sulfate or hydrogen peroxide, used to mimic the oxidative stress observed in AD-affected brains, potentiates Aβ-mediated perturbation of DNA damage/repair systems in the “Aβ cell line”. Taken together, these findings indicate that Aβ could act as double-edged sword by both increasing oxidative nuclear/mitochondrial damage and preventing its repair. The synergistic effects of increased ROS production, accumulated DNA damage and impaired DNA repair could participate in, and partly explain, the massive loss of neurons observed in Alzheimer’s disease since both oxidative stress and DNA damage can trigger apoptosis.

Published
2012

40. Effects of di(2-ethylhexyl)phthalate on testicular oxidant/antioxidant status in selenium-deficient and selenium-supplemented rats

Author

Filiz Hincal, Isabelle Hininger-Favier, Walid Rachidi, Pinar Erkekoglu, Anne-Marie Roussel, Belma Giray, and Alain Favier

Subjects
endocrine system, medicine.medical_specialty, GPX1, Antioxidant, Chemistry, Health, Toxicology and Mutagenesis, medicine.medical_treatment, General Medicine, Glutathione, Management, Monitoring, Policy and Law, Toxicology, GPX4, medicine.disease, medicine.disease_cause, Lipid peroxidation, chemistry.chemical_compound, Endocrinology, Biochemistry, Selenium deficiency, Internal medicine, medicine, TBARS, Oxidative stress
Abstract

Di(ethylhexyl)phthalate (DEHP), the most widely used plasticizer, was investigated to determine whether an oxidative stress process was one of the underlying mechanisms for its testicular toxicity potential. To evaluate the effects of selenium (Se), status on the toxicity of DEHP was further objective of this study, as Se is known to play a critical role in testis and in the modulation of intracellular redox equilibrium. Se deficiency was produced in 3-weeks-old Sprague-Dawley rats feeding them ≤0.05 mg Se /kg diet for 5 weeks, and Se-supplementation group was on 1 mg Se/kg diet. DEHP-treated groups received 1000 mg/kg dose by gavage during the last 10 days of the feeding period. Activities of antioxidant selenoenzymes [glutathione peroxidase 1 (GPx1), glutathione peroxidase 4 (GPx4), thioredoxin reductase (TrxR)], catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST); concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), and thus the GSH/GSSG redox ratio; and thiobarbituric acid reactive substance (TBARS) levels were measured. DEHP was found to induce oxidative stress in rat testis, as evidenced by significant decrease in GSH/GSSG redox ratio (>10-fold) and marked increase in TBARS levels, and its effects were more pronounced in Se-deficient rats with ∼18.5-fold decrease in GSH/GSSG redox ratio and a significant decrease in GPx4 activity, whereas Se supplementation was protective by providing substantial elevation of redox ratio and reducing the lipid peroxidation. These findings emphasized the critical role of Se as an effective redox regulator and the importance of Se status in protecting testicular tissue from the oxidant stressor activity of DEHP.

Published
2011
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41. Prion protein protects against zinc-mediated cytotoxicity by modifying intracellular exchangeable zinc and inducing metallothionein expression

Author

Fabrice Chimienti, Michel Seve, Pascale Guiraud, M’hammed Aouffen, Alain Favier, Walid Rachidi, and Abderrahmane Senator

Subjects
Cell Survival, animal diseases, Fluorescent Antibody Technique, chemistry.chemical_element, Zinc, Biology, Biochemistry, Cell Line, Inorganic Chemistry, Mice, Downregulation and upregulation, mental disorders, Gene expression, medicine, Animals, Metallothionein, PrPC Proteins, Neurodegeneration, Flow Cytometry, medicine.disease, Trace Elements, nervous system diseases, Gene Expression Regulation, chemistry, Cell culture, Molecular Medicine, Intracellular, Homeostasis
Abstract

PrPC contains several octapeptide repeats sequences toward the N-terminus which have binding affinity for divalent metals such as copper, zinc, nickel and manganese. However, the link between PrPC expression and zinc metabolism remains elusive. Here we studied the relationship between PrPC and zinc ions intracellular homeostasis using a cell line expressing a doxycycline-inducible PrPC gene. No significant difference in 65Zn2+ uptake was observed in cells expressing PrPC when compared with control cells. However, PrPC-expressing cells were more resistant to zinc-induced toxicity, suggesting an adaptative mechanism induced by PrPC. Using zinquin-ethyl-ester, a specific fluorophore for vesicular free zinc, we observed a significant re-localization of intracellular exchangeable zinc in vesicles after PrPC expression. Finally, we demonstrated that PrPC expression induces metallothionein (MT) expression, a zinc-upregulated zinc-binding protein. Taken together, these results suggest that PrPC modifies the intracellular localization of zinc rather than the cellular content and induces MT upregulation. These findings are of major importance since zinc deregulation is implicated in several neurodegenerative disorders. It is postulated that in prion diseases the conversion of PrPC to PrPSc may deregulate zinc homeostasis mediated by metallothionein.

Published
2009
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42. The effects of the cellular and infectious prion protein on the neuronal adaptor protein X11α

Author

Hilary E.M. McMahon, Nigel M. Hooper, Emma J. Comerford, Walid Rachidi, Jack O'Sullivan, and Michael Scott

Subjects
Phosphotyrosine binding, Prions, animal diseases, PDZ domain, Biophysics, Scrapie, Nerve Tissue Proteins, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Superoxide Dismutase-1, Cell Line, Tumor, Amyloid precursor protein, Animals, CASK, Molecular Biology, Cells, Cultured, 030304 developmental biology, Adaptor Proteins, Signal Transducing, 0303 health sciences, biology, Superoxide Dismutase, Signal transducing adaptor protein, nervous system diseases, Cell biology, Lymphocyte cytosolic protein 2, nervous system, Chaperone (protein), biology.protein, 030217 neurology & neurosurgery
Abstract

Background The neuronal adaptor protein X11α is a multidomain protein with a phosphotyrosine binding (PTB) domain, two PDZ (PSD_95, Drosophila disks-large, ZO-1) domains, a Munc Interacting (MI) domain and a CASK interacting region. Amongst its functions is a role in the regulation of the abnormal processing of the amyloid precursor protein (APP). It also regulates the activity of Cu/Zn Superoxide dismutase (SOD1) through binding with its chaperone the copper chaperone for SOD1. How X11α production is controlled has remained unclear. Methods Using the neuroblastoma cell line, N2a, and knockdown studies, the effect of the cellular and infectious prion protein, PrPC and PrPSc, on X11α is examined. Results We show that X11α expression is directly proportional to the expression of PrPC, whereas its levels are reduced by PrPSc. We also show PrPSc to affect X11α at a functional level. One of the effects of prion infection is lowered cellular SOD1 levels, here by knockdown of X11α we identify that the effect of PrPSc on SOD1 can be reversed indicating that X11α is involved in prion disease pathogenesis. Conclusions A role for the cellular and infectious prion protein, PrPC and PrPSc, respectively, in regulating X11α is identified in this work. General significance Due to the multiple interacting partners of X11α, dysfunction or alteration in X11α will have a significant cellular effect. This work highlights the role of PrPC and PrPSc in the regulation of X11α, and provides a new target pathway to control X11α and its related functions.

Published
2015

43. The Use of Gadolinium-based Nanoparticles to Improve Radiation Therapy Efficacy in HNSCC

Author

Stéphanie Simonet, Marie-Thérèse Aloy, Emma Armandy, Marc Janier, Olivier Tillement, François Lux, Michael Beuve, Jean-Luc Ravanat, Walid Rachidi, Claire Rodriguez-Lafrasse, Dominique Ardail, Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut Lumière Matière [Villeurbanne] (ILM), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut de Physique Nucléaire de Lyon (IPNL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

International audience; Head and neck squamous cell carcinoma (HNSCC) is an aggressive and recurrent malignancy owing to intrinsic radioresistance and lack of apoptosis induction. Several strategies aiming at radiosensitizing these tumors are currently being developed, one of which relies on the use of high Z elements nanoparticles such as gadolinium. Ultrasmall (5nm) gadolinium-based nanoparticles (GBNs) display properties, including stability, lack of toxicity, renal elimination, preferential accumulation in tumors (EPR effect) which make them a promising radiosensitizing tool. Once delivered to the tumor, GBNs amplify the efficacy of radiotherapy through the generation of secondary electrons leading to the overproduction of reactive oxygen species (ROS).

Published
2015

44. Study on the toxic mechanism of prion protein peptide 106–126 in neuronal and non neuronal cells

Author

Walid Rachidi, Willy Zorzi, Bernard Lhereux, Olivier Pierard, Ingrid Dupiereux, Danièle Zorzi, Benaïssa Elmoualij, and Ernst Heinen

Subjects
Central Nervous System, Programmed cell death, Prions, animal diseases, Transgene, Membrane lipids, Cell, Drug Resistance, Peptide, Biology, Transfection, Prion Diseases, Cell membrane, Membrane Lipids, Mice, Cellular and Molecular Neuroscience, Cell Line, Tumor, medicine, Animals, Humans, PrPC Proteins, Transgenes, Neurons, chemistry.chemical_classification, Cell Death, Cell Membrane, Epithelial Cells, Molecular biology, Peptide Fragments, nervous system diseases, medicine.anatomical_structure, chemistry, Cell culture, Nerve Degeneration, Rabbits
Abstract

A synthetic peptide corresponding to the 106-126 amyloidogenic region of the cellular human prion protein (PrP(c)) is useful for in vitro study of prion-induced neuronal cell death. The aim of the present work was to examine the implication of the cellular prion protein in the toxicity mechanism induced by PrP 106-126. The effect of PrP 106-126 was investigated both on human neuroblastoma SH-SY5Y cells and on SH-SY5Y overexpressing murine cellular prions (wtPrP). We show by metabolic assay tests and ATP assays that PrP(c) expression does not modulate the toxicity of the prion peptide. Moreover, we investigated the effect of this peptide on an established non neuronal model, rabbit kidney epithelial A74 cells that express a doxycycline-inducible murine PrP(c) gene. We show for the first time that the prion peptide 106-126 does not exert any toxic effect on this cell line in the presence or absence of doxycycline. Our results show that the PrP 106-126-induced cell alteration is independent of PrP(c) expression. Rather, it seems to act via an interaction with lipidic components of the plasma membrane as strengthened by our results showing the differential susceptibility of neuronal and non neuronal cell lines that significantly differ by their membrane fatty acid composition.

Published
2006
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45. Prion protein protects against DNA damage induced by paraquat in cultured cells

Author

Abderrahmane Senator, Mustapha Benboubetra, Walid Rachidi, Sylvain Lehmann, and Alain Favier

Subjects
Paraquat, DNA damage, Recombinant Fusion Proteins, Kidney, Transfection, medicine.disease_cause, Biochemistry, Lipid peroxidation, Superoxide dismutase, Mice, chemistry.chemical_compound, Malondialdehyde, Physiology (medical), medicine, Animals, PrPC Proteins, Cells, Cultured, chemistry.chemical_classification, Glutathione Peroxidase, Reactive oxygen species, biology, Superoxide Dismutase, Superoxide, Glutathione peroxidase, Epithelial Cells, Molecular biology, Oxidative Stress, Gene Expression Regulation, chemistry, Doxycycline, biology.protein, Rabbits, Oxidative stress, DNA Damage
Abstract

Exposure of cells to paraquat leads to production of superoxide anion (O 2 − ). This reacts with hydrogen peroxide to give the hydroxyl radical ( OH), leading to lipid peroxidation and cell death. In this study, we investigated the effects of cellular prion protein (PrP C ) overexpression on paraquat-induced toxicity by using an established model system, rabbit kidney epithelial A74 cells, which express a doxycycline-inducible murine PrP C gene. PrP C overexpression was found to significantly reduce paraquat-induced cell toxicity, DNA damage, and malondialdehyde acid levels. Superoxide dismutase (total SOD and CuZn-SOD) and glutathione peroxidase activities were higher in doxycycline-stimulated cells. Our findings clearly show that PrP C overexpression plays a protective role against paraquat toxicity, probably by virtue of its superoxide dismutase-like activity.

Published
2004
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46. Prion Infection Impairs Copper Binding of Cultured Cells

Author

Pascale Guiraud, Jacqueline Riondel, Alain Mangé, Walid Rachidi, Abderrahmene Senator, Sylvain Lehmann, Alain Favier, and Mustapha Benboubetra

Subjects
Prions, animal diseases, chemistry.chemical_element, Neuropathology, Biology, Phospholipase, Biochemistry, Prion Diseases, Phosphoinositide Phospholipase C, Copper binding, Prion infection, medicine, Humans, Prion protein, Molecular Biology, Cells, Cultured, Neurons, Phosphatidylinositol Diacylglycerol-Lyase, Neurodegeneration, Neurodegenerative Diseases, Cell Biology, medicine.disease, Copper, nervous system diseases, Cell biology, Kinetics, Copper Radioisotopes, chemistry, Type C Phospholipases, Molecular mechanism
Abstract

The molecular mechanism of neurodegeneration in transmissible spongiform encephalopathies (TSEs) remains unclear. Using radioactive copper ((64)Cu) at physiological concentration, we showed that prion infected cells display a marked reduction in copper binding. The level of full-length prion protein known to bind the metal ion was not modified in infected cells, but a fraction of this protein was not releasable from the membrane by phosphatidylinositol-specific phospholipase C. Our results suggest that prion infection modulates copper content at a cellular level and that modification of copper homeostasis plays a determinant role in the neuropathology of TSE.

Published
2003
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47. The effects of di(2-ethylhexyl) phthalate and/or selenium on trace element levels in different organs of rats

Author

Alain Favier, Belma Kocer-Gumusel, Josiane Arnaud, Filiz Hincal, Pinar Erkekoglu, Walid Rachidi, Department of Toxicology, Faculty of Pharmacy-Hacettepe University = Hacettepe Üniversitesi, Biochimie Hormonale et Nutritionnelle, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Hacettepe University = Hacettepe Üniversitesi-Faculty of Pharmacy, Département de biologie intégrée, CHU Grenoble-Hôpital Michallon, SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de biologie du stress oxydant, Université Joseph Fourier - Grenoble 1 (UJF), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), and Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Antioxidant, medicine.medical_treatment, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 010501 environmental sciences, Kidney, 01 natural sciences, Biochemistry, Rats, Sprague-Dawley, chemistry.chemical_compound, Selenium deficiency, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Testis, Tissue Distribution, Germ-Cell Apoptosis, ComputingMilieux_MISCELLANEOUS, [PHYS]Physics [physics], 0303 health sciences, Phthalate, 3. Good health, medicine.anatomical_structure, Liver, Organ Specificity, Toxicity, Trace element, Molecular Medicine, Reproductive toxicity, medicine.medical_specialty, endocrine system, chemistry.chemical_element, [SDV.CAN]Life Sciences [q-bio]/Cancer, Exposure, Inorganic Chemistry, Selenium, 03 medical and health sciences, Dietary Zinc, Selenium supplementation, Diethylhexyl Phthalate, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal medicine, medicine, Animals, Di-(2-Ethylhexyl) Phthalate, Mono-(2-Ethylhexyl) Phthalate, Testicular Atrophy, 030304 developmental biology, 0105 earth and related environmental sciences, Testicular atrophy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Rats, Trace Elements, Oxidative Stress, Endocrinology, chemistry, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer for synthetic polymers, is known to have endocrine disruptive potential, reproductive toxicity, and induces hepatic carcinogenesis in rodents. Selenium (Se) is a component of several selenoenzymes which are essential for cellular antioxidant defense and for the functions of mammalian reproductive system. The present study was designed to investigate the effects of DEHP exposure on trace element distribution in liver, testis, and kidney tissues and plasma of Se-deficient and Se-supplemented rats. Se deficiency was produced by feeding 3-week old Sprague-Dawley rats with

Published
2015
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48. Combination of Aβ Secretion and Oxidative Stress in an Alzheimer-Like Cell Line Leads to the Over-Expression of the Nucleotide Excision Repair Proteins DDB2 and XPC

Author

Viviana De Rosa, Thierry Douki, Walid Rachidi, Anne Forestier, David Béal, Rachidi, Walid, Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0063,PRIMES,Physique, Radiobiologie, Imagerie Médicale et Simulation(2011), Laboratoire de Chimie Inorganique et Biologique, SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, DDB2, Apoptosis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Chemistry, chemistry.chemical_compound, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], skin and connective tissue diseases, lcsh:QH301-705.5, Spectroscopy, ComputingMilieux_MISCELLANEOUS, Liver X Receptors, [PHYS]Physics [physics], Brain, Neurodegenerative Diseases, General Medicine, Base excision repair, Alzheimer's disease, Orphan Nuclear Receptors, Computer Science Applications, DNA-Binding Proteins, Mammalian-Cells, Deficiency, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Alzheimer’s disease, congenital, hereditary, and neonatal diseases and abnormalities, Mild Cognitive Impairment, Xeroderma pigmentosum, DNA damage, DNA repair, Ultraviolet Rays, XPC, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Catalysis, Article, Cell Line, Inorganic Chemistry, [SDV.CAN] Life Sciences [q-bio]/Cancer, Alzheimer Disease, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, Physical and Theoretical Chemistry, Molecular Biology, DNA-Damage, Amyloid beta-Peptides, Organic Chemistry, nutritional and metabolic diseases, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.disease, nucleotide excision repair, Molecular biology, Xeroderma-Pigmentosum, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Comet assay, Oxidative Stress, chemistry, lcsh:Biology (General), lcsh:QD1-999, Gene Expression Regulation, biological sciences, Neurodegenerative disorders, Lesions, DNA, Oxidative stress, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Nucleotide excision repair
Abstract

International audience; Repair of oxidative DNA damage, particularly Base Excision Repair (BER), impairment is often associated with Alzheimer's disease pathology. Here, we aimed at investigating the complete Nucleotide Excision Repair (NER), a DNA repair pathway involved in the removal of bulky DNA adducts, status in an Alzheimer-like cell line. The level of DNA damage was quantified using mass spectrometry, NER gene expression was assessed by qPCR, and the NER protein activity was analysed through a modified version of the COMET assay. Interestingly, we found that in the presence of the Amyloid peptide (A), NER factors were upregulated at the mRNA level and that NER capacities were also specifically increased following oxidative stress. Surprisingly, NER capacities were not differentially improved following a typical NER-triggering of ultraviolet C (UVC) stress. Oxidative stress generates a differential and specific DNA damage response in the presence of A. We hypothesized that the release of NER components such as DNA damage binding protein 2 (DDB2) and Xeroderma Pigmentosum complementation group C protein (XPC) following oxidative stress might putatively involve their apoptotic role rather than DNA repair function.

Published
2015
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49. The effects of di(2-ethylhexyl)phthalate on rat liver in relation to selenium status

Author

Naciye Dilara Zeybek, Belma Giray, Alain Favier, Walid Rachidi, Murat Kızılgün, Filiz Hincal, Esin Asan, Isabelle Hininger-Favier, Pinar Erkekoglu, Department of Toxicology, Hacettepe University = Hacettepe Üniversitesi-Faculty of Pharmacy, Faculty of Medicine [Hacettepe University], Hacettepe University = Hacettepe Üniversitesi, Laboratoire Lésions des Acides Nucléiques (LAN), Service de Chimie Inorganique et Biologique (SCIB - UMR E3), Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut Nanosciences et Cryogénie (INAC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS), SYstèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé (SYMMES), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Chimie Interface Biologie pour l’Environnement, la Santé et la Toxicologie (CIBEST ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Pediatric Genetics, Pediatric Hematology [Oncology Research & Training Hospital, Ankara, Turkey], Oncology Research & Training Hospital [Ankara], Lab Bioenerget Fondamentale & Appl, INSERM, U1055, Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de biologie du stress oxydant, Department of Histology and Embryology, Hacettepe University = Hacettepe Üniversitesi-Faculty of Medicine, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculty of Pharmacy-Hacettepe University = Hacettepe Üniversitesi, Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Rachidi, Walid

Subjects
Male, GPX1, Antioxidant, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Apoptosis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], 010501 environmental sciences, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, GPX4, 01 natural sciences, Rats, Sprague-Dawley, Lipid peroxidation, chemistry.chemical_compound, Selenium deficiency, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Phthalate, Catalase, 3. Good health, Liver, Biochemistry, Models, Animal, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], endocrine system, medicine.medical_specialty, chemistry.chemical_element, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Selenium, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Diethylhexyl Phthalate, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Peroxisomes, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Animals, Molecular Biology, 030304 developmental biology, 0105 earth and related environmental sciences, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Original Articles, Cell Biology, Glutathione, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.disease, Rats, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Oxidative Stress, Endocrinology, chemistry, Lipid Peroxidation, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; This study was performed to determine the hepatotoxicity of di(2‐ethylhexyl)phthalate (DEHP) in relation to selenium status. In 3‐week‐old Sprague‐Dawley rats, selenium deficiency was induced by a ≤0.05 selenium mg/kg. A selenium supplementation group was given 1 mg selenium/kg diet for 5 weeks. Di(2‐ethylhexyl)phthalate‐treated groups received 1000 mg/kg dose by gavage during the last 10 days of the experiment. Histopathology, peroxisome proliferation, catalase (CAT) immunoreactivity and activity and apoptosis were assessed. Activities of antioxidant selenoenzymes [glutathione peroxidase 1 (GPx1), glutathione peroxidase 4 (GPx4), thioredoxin reductase (TrxR1)], superoxide dismutase (SOD), and glutathione S‐transferase (GST); aminotransferase, total glutathione (tGSH), and lipid peroxidation (LP) levels were measured. Di(2‐ethylhexyl)phthalate caused cellular disorganization while necrosis and inflammatory cell infiltration were observed in Se‐deficient DEHP group (DEHP/SeD). Catalase activity and immunoreactivity were increased in all DEHP‐treated groups. Glutathione peroxidase 1 and GPx4 activities decreased significantly in DEHP and DEHP/SeD groups, while GST activities decreased in all DEHP‐exposed groups. Thioredoxin reductase activity increased in DEHP and DEHP/SeS, while total SOD activities increased in all DEHP‐treated groups. Lipid peroxidation levels increased significantly in SeD (26%), DEHP (38%) and DEHP/SeD (71%) groups. Selenium supplementation partially ameliorated DEHP‐induced hepatotoxicity; while in DEHP/SeD group, drastic changes in hepatic histopathology and oxidative stress parameters were observed.

Published
2014
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50. Adipose-derived Stem Cells Promote Skin Homeostasis and Prevent its Senescence in an In vitro Skin Model

Author

Odile Damour, Céline Auxenfans, Elodie Metral, Morgan Dos Santos, Walid Rachidi, Amélie Thépot, and Ali Mojallal

Subjects
Senescence, Pathology, medicine.medical_specialty, integumentary system, Epidermis (botany), Mesenchymal stem cell, Adipose tissue, Biology, Skin Aging, medicine.anatomical_structure, Dermis, medicine, Cancer research, Skin equivalent, Wound healing
Abstract

Objectives: Skin aging is subject of many studies in esthetic surgery including several morphological changes like decrease of epidermis thickness and of cell proliferative potential. ASC, mesenchymal stem cells derived from adipose tissue, have been used in regenerative and reparative surgery as well as anti-aging solution. The aim of this study was to highlight the influence of ASCs on skin aging and healing in an in vitro skin model. Methods: Using an skin equivalent (SE) model prepared without or with ASCs in different proportion (25% or 50% of ASCs), beneficial influence of ASCs on epidermal regeneration via markers of proliferative and differentiative potential and on quality of the dermis via markers of dermal protein synthesis was analyzed. In addition, an extendedtime cultured model mimicking skin ageing was used to demonstrate ASCs influence on skin aging via markers of the quality of the epidermis and dermis as well as via a marker of senescence. Results: After 42 days of culture, SEs prepared with 25% of ASCs were thicker, presented a better proliferative potential showed by a higher number of Ki67 positive cells, and a better differentiation in epidermis. A better fibroblast synthesis in dermis was also showed. Skin ageing was studied by prolonging culture time : SEs prepared with 25% of ASCs showed remained Ki67 positive cells and a low level of senescent marker, p16, labeling, whereas SEs with fibroblasts alone were very thin, free of proliferative cells and with a high p16 expression. Conclusions: To conclude, adding ASCs in low proportion (25%) improved quality of the epidermis and dermis preventing senescence of the SE model. This confirms clinical results and supports their anti-aging effect and their potential in wound healing. In addition, this model provides a tool to elucidate the mode of action of ASCs on healing and skin aging.

Published
2014
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