111 results on '"C Nicco"'
Search Results
2. Ultrasound-induced Cavitation enhances the efficacy of Chemotherapy in a 3D Model of Pancreatic Ductal Adenocarcinoma with its microenvironment
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R. Leenhardt, M. Camus, J. L. Mestas, M. Jeljeli, E. Abou Ali, S. Chouzenoux, B. Bordacahar, C. Nicco, F. Batteux, C. Lafon, F. Prat, Maladies fibro-inflammatoires d’origine métabolique et biliaire du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie Cellulaire, Université Paris Descartes - Paris 5 (UPD5), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)
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embryonic structures ,lcsh:R ,lcsh:Medicine ,lcsh:Q ,lcsh:Science ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is supported by a complex microenvironment whose physical contribution to chemoresistance could be overcome by ultrasound (US) therapy. This study aims to investigate the ability of US-induced inertial cavitation in association with chemotherapy to alter tumor cell viability via microenvironment disruption. For this purpose, we used a 3D-coculture PDAC model partially mimicking the tumor and its microenvironment. Coculture spheroids combining DT66066 cells isolated from KPC-transgenic mice and murine embryonic fibroblasts (iMEF) were obtained by using a magnetic nanoshuttle method. Spheroids were exposed to US with incremental inertial cavitation indexes. Conditions studied included control, gemcitabine, US-cavitation and US-cavitation + gemcitabine. Spheroid viability was assessed by the reduction of resazurin and flow cytometry. The 3D-coculture spheroid model incorporated activated fibroblasts and produced type 1-collagen, thus providing a partial miniature representation of tumors with their microenvironment. Main findings were: (a) Gemcitabine (5 μM) was significantly less cytotoxic in the presence of KPC/iMEFs spheroids compared with KPC (fibroblast-free) spheroids; (b) US-induced inertial cavitation combined with Gemcitabine significantly decreased spheroid viability compared to Gemcitabine alone; (c) both cavitation and chemotherapy affected KPC cell viability but not that of fibroblasts, confirming the protective role of the latter vis-à-vis tumor cells. Gemcitabine toxicity is enhanced when cocultured spheroids of KPC and iMEF are exposed to US-cavitation. Although the model used is only a partial representation of PDAC, this experience supports the hypothesis that US-inertial cavitation can enhance drug penetration and cytotoxicity by disrupting PDAC microenvironment.
- Published
- 2019
3. OP0307 Treatment of baff transgenic mice with ANTI-TNF: monoclonal ANTI-TNF are associated with a higher risk of lymphoma than etanercept
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G Nocturne, L Bineta, S Boudaoud, J Pascaud, R Seror, C Nicco, C Chereau, F Mackay, F Vincent, T Lazure, S Ferlicot, L Stimmer, S Roulland, R Krzysiek, S Hacein-Bey, F Batteux, and X Mariette
- Published
- 2017
4. Topical hemostatic powder promotes reepithelialization and reduces scar formation after extensive esophageal mucosal resection
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B, Beye, M, Barret, A, Alatawi, F, Beuvon, C, Nicco, C A, Pratico, C, Chereau, S, Chaussade, F, Batteux, and F, Prat
- Subjects
Minerals ,Esophageal Mucosa ,Endoscopic Mucosal Resection ,Swine ,Hemostatics ,Barrett Esophagus ,Cicatrix ,Esophagus ,Postoperative Complications ,Re-Epithelialization ,Esophageal Stenosis ,Animals ,Esophagoscopy ,Prospective Studies - Abstract
The development of techniques for endoscopic resection has provided new strategies for radical conservative treatment of superficial esophageal neoplasms, even those that are circumferential, such as Barrett's neoplasia. However, it is necessary to prevent the formation of scar tissue that can be responsible for esophageal strictures following circumferential resection. Preliminary data have suggested the possible efficacy of a hemostatic powder in the promotion of wound healing. The study aims to assess the effectiveness of Hemospray (Cook Medical) in a swine model of post-endoscopic esophageal stricture. Our prospective controlled study included 21 pigs. A 6-cm circumferential submucosal dissection of the esophagus (CESD) was performed in each pig. Group 1 (n = 11) only underwent CESD and Group 2 (n = 10) had repeated Hemospray applications after CESD. Clinical, endoscopic, and radiological monitoring were performed, blood levels of four inflammatory or pro-fibrotic cytokines were assessed, and histological analysis was performed. Median esophageal diameter was greater in the group treated with Hemospray (2 mm [1-3] vs. 3 mm [2-4], P = 0.01), and the rate of symptomatic esophageal stricture was 100% and 60% in Groups 1 and 2, respectively (P = 0.09). The thicknesses of esophageal fibrosis and inflammatory cell infiltrate were significantly lower in Group 2 than in Group 1 (P = 0.002 and 0.0003, respectively). The length of the neoepithelium was greater in Group 2 than in Group 1 (P = 0.0004). Transforming growth factor-β levels were significantly lower in Group 2 than in Group 1 (P = 0.01). The application of Hemospray after esophageal CESD reduces scar tissue formation and promotes reepithelialization, and therefore is a promising therapeutic approach in the prevention of post-endoscopic esophageal stricture.
- Published
- 2015
5. Genetic Variability of Rubisco in Tetraploid Wheats (Triticum turgidum)
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G. Cavalie, C. Nicco, A. Sarrafi, and M. Piquemal
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chemistry.chemical_classification ,biology ,fungi ,RuBisCO ,food and beverages ,Plant Science ,Phenotype ,Pyruvate carboxylase ,Enzyme ,chemistry ,Botany ,Genotype ,Genetics ,biology.protein ,Specific activity ,Cultivar ,Genetic variability ,Agronomy and Crop Science - Abstract
Nineteen tetraploid wheats (Triticum turgidum), differing in their agronomical behaviour and geographic origins were grown in two experiments and analysed for the following physiological traits: soluble leaf protein content, rubisco content, initial and potential carboxylase activities of this enzyme as well as its relative content in percentage of protein, the specific activity of the enzyme and its activation state. The results show a high genetic variability for all studied traits and more particularly for the initial carboxylase activity. High phenotypic correlation was observed between the rubisco content and its potential activities, in the first experiment. Correlation between souble leaf protein and rubisco content was significant in 9 genotypes of the second experiment.
- Published
- 1993
6. Rubisco Content and Specific Activity in Barley (Hordeum vulgareL.)
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C. Nicco, A. Sarrafi, G. Cavalie, M. Piquemal, and R. Ecochard
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biology ,Physiology ,fungi ,RuBisCO ,food and beverages ,Plant Science ,Photosynthesis ,biology.organism_classification ,Pyruvate carboxylase ,Seedling ,Botany ,biology.protein ,Poaceae ,Specific activity ,Hordeum vulgare ,Genetic variability - Abstract
Seven barley varieties, differing widely in their geographic origin, were analysed at the seedling stage under controlled conditions for the following traits: Soluble leaf protein content, Rubisco content, Total carboxylase activity, as well as for combinations of these basic characteristics: relative Rubisco concentration, relative carboxylase activity, and specific carboxylase activity of the enzyme
- Published
- 1991
7. Caractéristiques du polyomavirus de Merkel dans des lignées de carcinome à cellules de Merkel au cours du temps
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L Molet, F Batteux, C Nicco, B Vallette, Jean-Pierre Siffroi, L Cantero-Brassart, Alexander Valent, F Rozenberg, and Sandra Chantot-Bastaraud
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Medical Laboratory Technology ,Biochemistry (medical) ,Analytical Chemistry - Abstract
Le carcinome a cellules de Merkel est une tumeur neuroendocrine cutanee du sujet âge ou immunodeprime. Le genome du Polyomavirus de Merkel (MCPyV) est present dans la majorite des MCC etudies a ce jour. De plus, l’integration clonale du genome viral, la presence de mutations dans la sequence codant l’antigene LT, analogue de proteines oncogenes des Polyomavirus, et l’expression d’un Ag LT tronque suggerent l’implication du virus dans l’oncogenese. Cependant une minorite de MCC est depourvue de genome MCV. Ce phenomene pourrait s’expliquer par un mecanisme « hit and run », ou le virus via l’expression de la proteine LT induirait la tumorigenese, puis l’acquisition d’aberrations chromosomiques dans les cellules transformees permettrait a la fois de s’emanciper de l’expression de l’antigene LT et d’eliminer le genome viral. Trois lignees cellulaires ont ete etablies a partir de tissus MCC provenant de deux patients. L’integration du genome MCPyV a ete demontree dans les trois lignees en phase precoce de culture. Dans la lignee ganglionnaire metastatique du premier patient, l’integration et l’expression de la proteine LT ont persiste apres plusieurs mois en culture, les cellules injectees par voie sous cutanee a la souris scid-nod-gamma ont reproduit des tumeurs conservant ces memes caracteristiques au long cours. Malgre la perte en quelques semaines du genome viral de la lignee tumorale du second patient, la tumorigenese des cellules injectees a la souris etait conservee voire accrue par rapport au modele precedent. Deux modeles d’oncogenese ont donc ete etablis : le premier illustre l’oncogenese dependante de l’expression de l’Ag LT du MCPyV, tandis que le second semble illustrer l’oncogenese de type « hit and run » ou le genome viral initie la transformation cellulaire puis est elimine.
- Published
- 2014
8. IBPA a mutual prodrug of ibuprofen and acetaminophen alleviates inflammation, immune dysregulation and fibrosis in preclinical models of systemic sclerosis.
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Rodrigues de Almeida A, Jaime Bezerra Mendonça Junior F, Tavares Dantas A, Eduarda de Oliveira Gonçalves M, Chêne C, Jeljeli M, Chouzenoux S, Thomas M, David de Azevedo Valadares L, Andreza Bezerra Correia M, Ângela da Silva Alves W, Carvalho Lira E, Doridot L, Jesus Barreto de Melo Rêgo M, Cristiny Pereira M, Luzia Branco Pinto Duarte A, Saes Parra Abdalla D, Nicco C, Batteux F, and Galdino da Rocha Pitta M
- Subjects
- Animals, Humans, Female, Mice, Male, Middle Aged, Inflammation drug therapy, Cells, Cultured, Skin drug effects, Skin pathology, Skin immunology, Hypochlorous Acid, Adult, Prodrugs therapeutic use, Prodrugs pharmacology, Mice, Inbred BALB C, Acetaminophen pharmacology, Scleroderma, Systemic drug therapy, Scleroderma, Systemic immunology, Scleroderma, Systemic pathology, Ibuprofen therapeutic use, Ibuprofen pharmacology, Cytokines metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Fibrosis drug therapy, Disease Models, Animal
- Abstract
Systemic sclerosis (SSc) is a devastating autoimmune illness with a wide range of clinical symptoms, including vascular abnormalities, inflammation, and persistent and progressive fibrosis. The disease's complicated pathophysiology makes it difficult to develop effective therapies, necessitating research into novel therapeutic options. Molecular hybridization is a strategy that can be used to develop new drugs that act on two or multiple targets and represents an interesting option to be explored for the treatment of complex diseases. We aimed to evaluate the effects of a hybrid mutual prodrug of ibuprofen and acetaminophen (IBPA) in peripheral blood mononuclear cells (PBMC) isolated from SSc patients, and in an in vivo model of SSc induced in BALB/c mice by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. The mice were treated at the same time with daily intraperitoneal injections of IBPA (40 mg/kg). Pulmonary and skin fibrosis as well as immune responses were evaluated. IBPA significantly decreased the release of cytokines in PBMC culture supernatants from SSc patients after stimulation with phytohemagglutinin-M (IL-2, IL-4, IL-6, IL-10, IL-13, IL-17A, TNF and IFN-γ).In HOCl-induced SSc, IBPA treatment prevented dermal and pulmonary fibrosis, in addition to reducing CD4 + T and B cells activation and reversing the M2 polarization of macrophages in spleen cells, and inhibiting IFN-γ secretion in splenocyte cultures. These results show the anti-inflammatory and antifibrotic effects of IBPA in SSc and highlight the therapeutic potential of this mutual prodrug, providing support for future studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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9. The Potential of Twendee X ® as a Safe Antioxidant Treatment for Systemic Sclerosis.
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You F, Nicco C, Harakawa Y, Yoshikawa T, and Inufusa H
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- Humans, Mice, Animals, Dietary Supplements, Fibrosis, Skin metabolism, Disease Models, Animal, Antioxidants pharmacology, Scleroderma, Systemic metabolism, Ascorbic Acid, Cystine, Glutamine
- Abstract
Systemic sclerosis (SSc) is an autoimmune disease characterized by systemic skin hardening, which combines Raynaud's phenomenon and other vascular disorders, skin and internal organ fibrosis, immune disorders, and a variety of other abnormalities. Symptoms vary widely among individuals, and personalized treatment is sought for each patient. Since there is no fundamental cure for SSc, it is designated as an intractable disease with patients receiving government subsidies for medical expenses in Japan. Oxidative stress (OS) has been reported to play an important role in the cause and symptoms of SSc. HOCl-induced SSc mouse models are known to exhibit skin and visceral fibrosis, vascular damage, and autoimmune-like symptoms observed in human SSc. The antioxidant combination Twendee X
® (TwX) is a dietary supplement consisting of vitamins, amino acids, and CoQ10. TwX has been proven to prevent dementia in humans with mild cognitive impairment and significantly improve cognitive impairment in an Alzheimer's disease mouse model by regulating OS through a strong antioxidant capacity that cannot be achieved with a single antioxidant ingredient. We evaluated the effectiveness of TwX on various symptoms of HOCl-induced SSc mice. TwX-treated HOCl-induced SSc mice showed significantly reduced lung and skin fibrosis compared to untreated HOCl-induced SSc mice. TwX also significantly reduced highly oxidized protein products (AOPP) in serum and suppressed Col-1 gene expression and activation of B cells involved in autoimmunity. These findings suggest that TwX has the potential to be a new antioxidant treatment for SSc without side effects.- Published
- 2024
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10. PPARγ partial agonist LPSF/GQ-16 prevents dermal and pulmonary fibrosis in HOCl-induced systemic sclerosis (SSc) and modulates cytokine production in PBMC of SSc patients.
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de Almeida AR, Dantas AT, de Oliveira Gonçalves ME, Chêne C, Jeljeli M, Chouzenoux S, Thomas M, Cunha EGC, de Azevedo Valadares LD, de Melo Gomes JV, de Paula SKS, da Rocha Pitta MG, da Rocha Pitta I, de Melo Rêgo MJB, Pereira MC, Duarte ALBP, Abdalla DSP, Nicco C, Batteux F, and da Rocha Pitta MG
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- Humans, Animals, Mice, Leukocytes, Mononuclear, Hypochlorous Acid, PPAR gamma, Cytokines, Pulmonary Fibrosis chemically induced, Pulmonary Fibrosis drug therapy, Scleroderma, Systemic chemically induced, Scleroderma, Systemic drug therapy, Thiazolidinediones
- Abstract
Thiazolidinediones (TZD) are synthetic molecules that have a range of biological effects, including antifibrotic and anti-inflammatory, and they may represent a promising therapeutic strategy for systemic sclerosis (SSc). The aim of this study was to investigate the immunomodulatory and antifibrotic properties of LPSF/GQ-16, a TZD derivative, in peripheral blood mononuclear cells (PBMC) from SSc patients and in a murine model of SSc HOCl-induced. The PBMC of 20 SSc patients were stimulated with phytohemagglutinin (PHA) and treated with LPSF/GQ-16 for 48 h, later cytokines in the culture supernatants were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA). Experimental SSc was induced by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. HOCl-induced SSc mice received daily treatment with LPSF/GQ-16 (30 mg/kg) through intraperitoneal injections during the same period. Immunological parameters were evaluated by flow cytometry and ELISA, and dermal and pulmonary fibrosis were evaluated by RT-qPCR, hydroxyproline dosage and histopathological analysis. In PBMC cultures, it was possible to observe that LPSF/GQ-16 modulated the secretion of cytokines IL-2 (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.001), IL-17A (p = 0.006), TNF (p < 0.001) and IFN-γ (p < 0.001). In addition, treatment with LPSF/GQ-16 in HOCl-induced SSc mice promoted a significant reduction in dermal thickening (p < 0.001), in the accumulation of collagen in the skin (p < 0.001), down-regulated the expression of fibrosis markers in the skin (Col1a1, α-Sma and Tgfβ1, p < 0.001 for all) and lungs (Il4 and Il13, p < 0.001 for both), as well as reduced activation of CD4 + T cells (p < 0.001), B cells (p < 0.001) and M2 macrophages (p < 0.001). In conclusion, LPSF/GQ-16 showed immunomodulatory and antifibrotic properties, demonstrating the therapeutic potential of this molecule for SSc., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2024
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11. Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD.
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Raman D, Chêne C, Nicco C, Jeljeli M, Eu JQ, Clément MV, Batteux F, and Pervaiz S
- Abstract
Graft-versus-host disease (GVHD) is a life-threatening systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by dysregulation of T and B cell activation and function, scleroderma-like features, and multi-organ pathology. The treatment of cGVHD is limited to the management of symptoms and long-term use of immunosuppressive therapy, which underscores the need for developing novel treatment approaches. Notably, there is a striking similarity between cytokines/chemokines responsible for multi-organ damage in cGVHD and pro-inflammatory factors, immune modulators, and growth factors secreted by senescent cells upon the acquisition of senescence-associated secretory phenotype (SASP). In this pilot study, we questioned the involvement of senescent cell-derived factors in the pathogenesis of cGVHD triggered upon allogeneic transplantation in an irradiated host. Using a murine model that recapitulates sclerodermatous cGVHD, we investigated the therapeutic efficacy of a senolytic combination of dasatinib and quercetin (DQ) administered after 10 days of allogeneic transplantation and given every 7 days for 35 days. Treatment with DQ resulted in a significant improvement in several physical and tissue-specific features, such as alopecia and earlobe thickness, associated with cGVHD pathogenesis in allograft recipients. DQ also mitigated cGVHD-associated changes in the peripheral T cell pool and serum levels of SASP-like cytokines, such as IL-4, IL-6 and IL-8Rα. Our results support the involvement of senescent cells in the pathogenesis of cGVHD and provide a rationale for the use of DQ, a clinically approved senolytic approach, as a potential therapeutic strategy.
- Published
- 2023
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12. Optimal combination of arsenic trioxide and copper ions to prevent autoimmunity in a murine HOCl-induced model of systemic sclerosis.
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Chêne C, Rongvaux-Gaïda D, Thomas M, Rieger F, Nicco C, and Batteux F
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- Humans, Animals, Mice, Arsenic Trioxide, Reactive Oxygen Species metabolism, Autoimmunity, Hydrogen Peroxide metabolism, Fibrosis, Copper, Scleroderma, Systemic chemically induced, Scleroderma, Systemic drug therapy, Scleroderma, Systemic metabolism
- Abstract
Introduction: Systemic sclerosis (SSc) is a rare chronic autoimmune disease characterized by diffuse fibrosis of the skin and internal organs and vascular abnormalities. The etiology and physiopathology are complex due to the heterogeneity of its overall clinical presentation. Arsenic trioxide (ATO) has been proven to be effective against SSc, sclerodermatous Graft-versus-Host Disease, multiple sclerosis, Crohn's disease or systemic lupus erythematosus animal models and has demonstrated promising effects in human clinical trials. Its efficacy was shown to be related at least in part to the generation of Reactive Oxygen Species (ROS) and the selective deletion of activated immune cells and fibroblasts. However, ATO can induce some adverse effects that must be considered, especially when used for the treatment of a chronic disease., Methods: We evaluate here, in vitro and in a mouse model of SSc, the improved efficacy of ATO when associated with a Fenton-like divalent cation, namely copper chloride (CuCl
2 ), also known to trigger the production of ROS., Results: In preliminary experiments in vitro , ATO 1 µM + CuCl2 0.5 µM increased ROS production and increased apoptosis of NIH 3T3 murine fibroblasts compared to 1 µM ATO alone. In vivo , in the HOCl-induced mouse model of SSc, co-treatment with ATO 2.5 μg/g + CuCl2 0.5 μg/g significantly alleviated clinical signs such as the thickening of the skin (p<0.01) and cutaneous fibrosis, in a manner equivalent to treatment with ATO 5 µg/g. Our results provide evidence that co-treatment with ATO 2.5 μg/g + CuCl2 0.5 μg/g decreases the number of B cells and the activation of CD4+ T lymphocytes. The co-treatment substantially blocks the NRF2 signaling pathway, increases H2O2 production and results in the improvement of the health status of mice with experimental SSc., Conclusion: In conclusion, copper combined with ATO treatment halved the concentration of ATO needed to obtain the same effect as a high dose of ATO alone for the treatment of SSc mice. The strategy of using lower doses of drugs with different mechanisms of action in combination has many potential advantages, the first being to lessen the potential side effects induced by ATO, a drug with side effects quickly increased with dosage., Competing Interests: FR and FB are listed as inventors for an early patent application family designation relative to the synergic use of arsenic salts and metallic ions for the treatment of autoimmune diseases. DR-G and FR are currently employees of MEDSENIC SAS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Chêne, Rongvaux-Gaïda, Thomas, Rieger, Nicco and Batteux.)- Published
- 2023
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13. Mechanistic target of rapamycin (mTOR) regulates self-sustained quiescence, tumor indolence, and late clinical metastasis in a Beclin-1-dependent manner.
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Nicco C, Thomas M, Guillermet J, Havard M, Laurent-Tchenio F, Doridot L, Dautry F, Batteux F, and Tchenio T
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- Male, Animals, Mice, Beclin-1 genetics, TOR Serine-Threonine Kinases metabolism, Sirolimus, Cell Proliferation, RNA, Messenger, Cell Line, Tumor, Pancreatic Neoplasms, Adenocarcinoma pathology, Pancreatic Neoplasms pathology
- Abstract
Self-sustained quiescence (SSQ) has been characterized as a stable but reversible non-proliferative cellular state that limits the cloning of cultured cancer cells. By developing refined clonogenic assays, we showed here that cancer cells in SSQ can be selected with anticancer agents and that culture at low cell density induced SSQ in pancreas and prostate adenocarcinoma cells. Pre-culture of cells in 3D or their pretreatment with pharmacological inhibitors of mechanistic target of rapamycin (mTOR) synergize with low cell density for induction of SSQ in a Beclin-1-dependent manner. Dissociated pancreatic adenocarcinoma (PAAD) cells rendered defective for SSQ by down-regulating Beclin-1 expression exhibit higher tumor growth rate when injected subcutaneously into mice. Conversely, dissociated PAAD cells in SSQ promote the formation of small indolent tumors that eventually transitioned to a rapid growth phase. Ex vivo clonogenic assays showed that up to 40% of clonogenic cancer cells enzymatically dissociated from resected fast-growing tumors could enter SSQ, suggesting that SSQ could significantly impact the proliferation of cancer cells that are naturally dispersed from tumors. Remarkably, the kinetics of clinical metastatic recurrence in 124 patients with pancreatic adenocarcinoma included in the TGCA-PAAD project could be predicted from Beclin-1 and Cyclin-A2 mRNA levels in their primary tumor, Cyclin A2 mRNA being a marker of both cell proliferation and mTOR complex 1 activity. Overall, our data show that SSQ is likely to promote the late development of clinical metastases and suggest that identifying new agents targeting cancer cells in SSQ could help improve patient survival.
- Published
- 2023
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14. Mechanisms of esophageal stricture after extensive endoscopic resection: a transcriptomic analysis.
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Barret M, Doridot L, Le Gall M, Beuvon F, Jacques S, Pellat A, Belle A, Abou Ali E, Dhooge M, Leblanc S, Camus M, Nicco C, Coriat R, Chaussade S, Batteux F, and Prat F
- Abstract
Background and study aims Esophageal stricture is the most frequent adverse event after endoscopic resection for early esophageal neoplasia. Currently available treatments for the prevention of esophageal stricture are poorly effective and associated with major adverse events. Our aim was to identify transcripts specifically overexpressed or repressed in patients who have developed a post-endoscopic esophageal stricture, as potential targets for stricture prevention. Patients and methods We conducted a prospective single-center study in a tertiary endoscopy center. Patients scheduled for an endoscopic resection and considered at risk of esophageal stricture were offered inclusion in the study. The healthy mucosa and resection bed were biopsied on Days 0, 14, and 90. A transcriptomic analysis by microarray was performed, and the differences in transcriptomic profile compared between patients with and without esophageal strictures. Results Eight patients, four with esophageal stricture and four without, were analyzed. The mean ± SD circumferential extension of the mucosal defect was 85 ± 11 %. The transcriptomic analysis in the resection bed at day 14 found an activation of the interleukin (IL)-1 group (Z score = 2.159, P = 0.0137), while interferon-gamma (INFγ) and NUPR1 were inhibited (Z score = -2.375, P = 0.0022 and Z score = -2.333, P = 0.00131) in the stricture group. None of the activated or inhibited transcripts were still significantly so in any of the groups on Day 90. Conclusions Our data suggest that IL-1 inhibition or INFγ supplementation could constitute promising targets for post-endoscopic esophageal stricture prevention., Competing Interests: Competing interests M Barret: Medtronic, olympus (medical training), Dr Falk pharma (oral presentation), Norgine, Ambu (board participation); The other authors declared that they do not have any conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)
- Published
- 2023
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15. A New Manganese Superoxide Dismutase Mimetic Improves Oxaliplatin-Induced Neuropathy and Global Tolerance in Mice.
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Prieux-Klotz C, Chédotal H, Zoumpoulaki M, Chouzenoux S, Chêne C, Lopez-Sanchez A, Thomas M, Ranjan Sahoo P, Policar C, Batteux F, Bertrand HC, Nicco C, and Coriat R
- Subjects
- Mice, Animals, Oxaliplatin adverse effects, Reactive Oxygen Species metabolism, Hydrogen Peroxide metabolism, Superoxides, Superoxide Dismutase, Mice, Inbred BALB C, Antineoplastic Agents therapeutic use, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases drug therapy, Peripheral Nervous System Diseases pathology
- Abstract
Reactive oxygen species (ROS) are produced by every aerobic cell during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Superoxide Dismutases (SOD) are antioxidant proteins that convert superoxide anions (O
2 •- ) to hydrogen peroxide (H2 ) and dioxygen. Using the differential in the level of oxidative stress between normal and cancer cells, SOD mimetics can show an antitumoral effect and prevent oxaliplatin-induced peripheral neuropathy. New Pt(IV) conjugate prodrugs (OxPt-x-Mn1C1A (x = 1, 1-OH, 2)), combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, were designed. Their stability in buffer and in the presence of sodium ascorbate was studied. In vitro, their antitumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3). In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells in Balb/c mice. Tumor size and volume were measured weekly in four groups: vehicle, oxaliplatin, and oxaliplatin associated with MnSODm Mn1C1A and the bis-conjugate OxPt-2-Mn1C1A. Oxaliplatin-induced peripheral neuropathy (OIPN) was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including four items: weight loss, weariness, alopecia, and diarrhea. In vitro, Mn1C1A associated with oxaliplatin and Pt(IV) conjugates treatment induced significantly higher production of H2 ) and dioxygen. Using the differential in the level of oxidative stress between normal and cancer cells, SOD mimetics can show an antitumoral effect and prevent oxaliplatin-induced peripheral neuropathy. New Pt(IV) conjugate prodrugs (OxPt-x-Mn1C1A (x = 1, 1-OH, 2)), combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, were designed. Their stability in buffer and in the presence of sodium ascorbate was studied. In vitro, their antitumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3). In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells in Balb/c mice. Tumor size and volume were measured weekly in four groups: vehicle, oxaliplatin, and oxaliplatin associated with MnSODm Mn1C1A and the bis-conjugate OxPt-2-Mn1C1A. Oxaliplatin-induced peripheral neuropathy (OIPN) was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including four items: weight loss, weariness, alopecia, and diarrhea. In vitro, Mn1C1A associated with oxaliplatin and Pt(IV) conjugates treatment induced significantly higher production of H2 O2 in all cell lines and showed a significant improvement of the antitumoral efficacy compared to oxaliplatin alone. In vivo, the association of Mn1C1A to oxaliplatin did not decrease its antitumoral activity, while OxPt-2-Mn1C1A had lower antitumoral activity than oxaliplatin alone. Mn1C1A associated with oxaliplatin significantly decreased OIPN and also improved global clinical tolerance of oxaliplatin. A neuroprotective effect was observed, associated with a significantly improved tolerance to oxaliplatin without impairing its antitumoral activity.- Published
- 2022
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16. A Fenton-like cation can improve arsenic trioxide treatment of sclerodermatous chronic Graft-versus-Host Disease in mice.
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Chêne C, Jeljeli MM, Rongvaux-Gaïda D, Thomas M, Rieger F, Batteux F, and Nicco C
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- Animals, Arsenic Trioxide pharmacology, Cations, Fibrosis, Humans, Mice, Oxides pharmacology, Arsenicals pharmacology, Arsenicals therapeutic use, Graft vs Host Disease drug therapy, Graft vs Host Disease etiology
- Abstract
Graft-versus Host Disease (GvHD) is a major complication of hematopoietic stem cell transplant. GvHD is characterized by the chronic activation of immune cells leading to the development of systemic inflammation, autoimmunity, fibrosis and eventually death. Arsenic trioxide (ATO) is a therapeutic agent under clinical trial for the treatment of patients with systemic lupus erythematosus (SLE) and chronic GvHD (cGvHD). This therapy is admittedly rather safe although adverse effects can occur and may necessitate short interruptions of the treatment. The aim of this study was to combine ATO with a divalent cation, to generate a Fenton or Fenton-like reaction in order to potentiate the deletion of activated immune cells through the reactive oxygen species (ROS)-mediated effects of ATO in a mouse model, and thereby enabling the use of lower and safer ATO concentrations to treat patients with cGvHD. In vitro , among the various combinations of divalent cations tested, we observed that the combination of ATO and CuCl
2 (copper chloride) induced a high level of oxidative stress in HL-60 and A20 cells. In addition, this co-treatment also decreased the proliferation of CD4+ T lymphocytes during a mixed lymphocyte reaction (MLR). In vivo , in a cGvHD mouse model, daily injections of ATO 2.5 µg/g + CuCl2 0.5 µg/g induce a decrease in lymphocyte activation and fibrosis that was equivalent to that induced by ATO 5 µg/g. Our results show that the addition of CuCl2 improved the effects of ATO and significantly limited the development of the disease. This co-treatment could be a real benefit in human patients to substantially decrease the known ATO side effects and optimize ATO treatment in pathologies characterized by activated cells sensitive to an increase in oxidative stress., Competing Interests: FR and FB are listed inventors for an early patent application family (designation) relative to the synergic use of arsenic salts and metallic ions for the treatment of autoimmune diseases. DR-G and FR are currently employees of MEDSENIC SAS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chêne, Jeljeli, Rongvaux-Gaïda, Thomas, Rieger, Batteux and Nicco.)- Published
- 2022
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17. BCG-trained innate immunity leads to fetal growth restriction by altering immune cell profile in the mouse developing placenta.
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Dang Y, Souchet C, Moresi F, Jeljeli M, Raquillet B, Nicco C, Chouzenoux S, Lagoutte I, Marcellin L, Batteux F, and Doridot L
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- Animals, Female, Fetal Growth Retardation, Fetal Resorption, Humans, Immunity, Innate, Mice, Mice, Inbred CBA, Mice, Inbred DBA, Placenta, Pregnancy, BCG Vaccine, Mycobacterium bovis
- Abstract
Trained immunity is a new concept illustrating that innate immune cells are able to undergo a long-term metabolic and epigenetic reprogramming after infection or vaccination, thus displaying either a pro- or an anti-inflammatory phenotype during a sequential unrelated challenge. Innate immune cells such as natural killer (NK) cells and macrophages constitute a large part of the decidual leukocyte population at the maternal-fetal interface, playing an important role in placental development and as such in fetal growth and development. In this study, we hypothesized that training the innate immune cells before pregnancy could have an impact on pregnancy. To test this hypothesis, we used CBA/J x DBA/2 mouse model to investigate pregnancy outcomes and leukocyte population at the maternal-fetal interface. Although we were not able to show a beneficial effect of LPS-tolerogenic training on fetal resorption, Bacillus Calmette-Guérin (BCG) training, known to prime innate immune cells to be proinflammatory, led to fetal growth restriction, without aggravating the fetal resorption rate. We also found that BCG training led to less NK cells and macrophages at the maternal-fetal interface at the early stage of placentation (E9.5), associated with a down-regulation of Ccr3 and Lif mRNA expression. This induced altered leucocyte population profile can be an explanation for the subsequent fetal growth restriction. These data suggest that preconceptional infections-induced trained immunity could influence pregnancy outcomes., (©2021 Society for Leukocyte Biology.)
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- 2022
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18. A New Topical Candidate in Acne Treatment: Characterization of the Meclozine Hydrochloride as an Anti-Inflammatory Compound from In Vitro to a Preliminary Clinical Study.
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Grange PA, Ollagnier G, Beauvais Remigereau L, Nicco C, Mayslich C, Marcelin AG, Calvez V, and Dupin N
- Abstract
Acne is a chronic inflammatory multifactorial disease involving the anaerobic bacterium Cutibacterium acnes (C. acnes). Current acne treatments are associated with adverse effects, limiting treatment compliance and use. We showed that meclozine, an anti-histaminic H1 compound, has anti-inflammatory properties. In Vitro, meclozine reduced the production of CXCL8/IL-8 and IL-1β mRNA and protein by C. acnes-stimulated human keratinocytes and monocytes. No cell toxicity was observed at the IC50. Meclozine prevented the phosphorylation of ERK and JNK. In Vivo, 1% meclozine gel significantly decreased C. acnes-mouse ear induced inflammation by 26.7% (p = 0.021). Ex vivo experiments on human skin explants showed that meclozine decreased the production of GM-CSF, IL-1β and TNF-α at transcriptional and translational levels. In a randomized, double-blind, placebo-controlled proof-of-concept clinical trial on 60 volunteers, 2% meclozine pharmaceutical gel decreased by 20.1% (p < 0.001) the ASI score in the treated group after 12 weeks of treatment. No adverse event was reported. Together, these results indicate that meclozine is a potent topical anti-inflammatory compound of potential value for acne treatment.
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- 2022
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19. Microbiota medicine: towards clinical revolution.
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Gebrayel P, Nicco C, Al Khodor S, Bilinski J, Caselli E, Comelli EM, Egert M, Giaroni C, Karpinski TM, Loniewski I, Mulak A, Reygner J, Samczuk P, Serino M, Sikora M, Terranegra A, Ufnal M, Villeger R, Pichon C, Konturek P, and Edeas M
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- Dysbiosis therapy, Gastrointestinal Tract, Humans, Prebiotics, Gastrointestinal Microbiome, Microbiota, Probiotics therapeutic use
- Abstract
The human gastrointestinal tract is inhabited by the largest microbial community within the human body consisting of trillions of microbes called gut microbiota. The normal flora is the site of many physiological functions such as enhancing the host immunity, participating in the nutrient absorption and protecting the body against pathogenic microorganisms. Numerous investigations showed a bidirectional interplay between gut microbiota and many organs within the human body such as the intestines, the lungs, the brain, and the skin. Large body of evidence demonstrated, more than a decade ago, that the gut microbial alteration is a key factor in the pathogenesis of many local and systemic disorders. In this regard, a deep understanding of the mechanisms involved in the gut microbial symbiosis/dysbiosis is crucial for the clinical and health field. We review the most recent studies on the involvement of gut microbiota in the pathogenesis of many diseases. We also elaborate the different strategies used to manipulate the gut microbiota in the prevention and treatment of disorders. The future of medicine is strongly related to the quality of our microbiota. Targeting microbiota dysbiosis will be a huge challenge., (© 2022. The Author(s).)
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- 2022
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20. Acazicolcept (ALPN-101), a dual ICOS/CD28 antagonist, demonstrates efficacy in systemic sclerosis preclinical mouse models.
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Orvain C, Cauvet A, Prudent A, Guignabert C, Thuillet R, Ottaviani M, Tu L, Duhalde F, Nicco C, Batteux F, Avouac J, Wang N, Seaberg MA, Dillon SR, and Allanore Y
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- Animals, CD28 Antigens metabolism, Disease Models, Animal, Humans, Inducible T-Cell Co-Stimulator Protein metabolism, Mice, Mice, Transgenic, Pulmonary Fibrosis metabolism, Skin pathology, CD28 Antigens antagonists & inhibitors, Inducible T-Cell Co-Stimulator Protein antagonists & inhibitors, Scleroderma, Systemic drug therapy, Scleroderma, Systemic pathology, Single-Chain Antibodies pharmacology
- Abstract
Background: Uncontrolled immune response with T cell activation has a key role in the pathogenesis of systemic sclerosis (SSc), a disorder that is characterized by generalized fibrosis affecting particularly the lungs and skin. Costimulatory molecules are key players during immune activation, and recent evidence supports a role of CD28 and ICOS in the development of fibrosis. We herein investigated the efficacy of acazicolcept (ALPN-101), a dual ICOS/CD28 antagonist, in two complementary SSc-related mouse models recapitulating skin fibrosis, interstitial lung disease, and pulmonary hypertension., Methods: Expression of circulating soluble ICOS and skin-expressed ICOS was investigated in SSc patients. Thereafter, acazicolcept was evaluated in the hypochlorous acid (HOCL)-induced dermal fibrosis mouse model and in the Fra-2 transgenic (Tg) mouse model. In each model, mice received 400 μg of acazicolcept or a molar-matched dose of an Fc control protein twice a week for 6 weeks. After 6 weeks, skin and lung were evaluated., Results: ICOS was significantly increased in the sera from SSc patients and in SSc skin biopsies as compared to samples from healthy controls. Similar body weight changes were observed between Fc control and acazicolcept groups in both HOCL and Fra-2 Tg mice suggesting a good tolerance of acazicolcept treatment. In mice challenged with HOCL, acazicolcept induced a significant decrease in dermal thickness, collagen content, myofibroblast number, and inflammatory infiltrates characterized by B cells, T cells, neutrophils, and macrophages. In the Fra-2 Tg mouse model, acazicolcept treatment reduced lung collagen content, fibrillar collagen, histological fibrosis score, and right ventricular systolic pressure (RVSP). A reduction in frequency of CD4+ and T effector memory cells and an increase in the percentage of CD4+ T naïve cells in spleen and lung of acazicolcept-treated Fra-2 Tg mice was observed as compared to Fc control-treated Fra-2 Tg mice. Moreover, acazicolcept reduced CD69 and PD-1 expression on CD4+ T cells from the spleen and the lung. Target engagement by acazicolcept was demonstrated by blockade of CD28 and ICOS detection by flow cytometry in treated mice., Conclusions: Our results confirm the importance of costimulatory molecules in inflammatory-driven fibrosis. Our data highlight a key role of ICOS and CD28 in SSc. Using complementary models, we demonstrated that dual ICOS/CD28 blockade by acazicolcept decreased dermal and pulmonary fibrosis and alleviated pulmonary hypertension. These results pave the way for subsequent research on ICOS/CD28-targeted therapies., (© 2021. The Author(s).)
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- 2022
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21. Therapeutic Potential of Anti-Interferon α Vaccination on SjS-Related Features in the MRL/lpr Autoimmune Mouse Model.
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Killian M, Colaone F, Haumont P, Nicco C, Cerles O, Chouzenoux S, Cathébras P, Rochereau N, Chanut B, Thomas M, Laroche N, Forest F, Grouard-Vogel G, Batteux F, and Paul S
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- Animals, Antibodies, Neutralizing blood, Autoantibodies blood, Autoimmunity, B-Lymphocytes immunology, Disease Models, Animal, Female, Gene Expression Profiling, Hemocyanins administration & dosage, Hemocyanins immunology, Humans, Immunoconjugates administration & dosage, Immunoconjugates immunology, Immunotherapy, Active, Interferon-alpha administration & dosage, Interferon-alpha immunology, Interferons biosynthesis, Interferons genetics, Lacrimal Apparatus immunology, Lacrimal Apparatus pathology, Mice, Mice, Inbred MRL lpr, Salivary Glands immunology, Salivary Glands pathology, Sjogren's Syndrome genetics, Interferon-alpha antagonists & inhibitors, Sjogren's Syndrome immunology, Sjogren's Syndrome therapy
- Abstract
Sjögren's syndrome (SjS) is a frequent systemic autoimmune disease responsible for a major decrease in patients' quality of life, potentially leading to life-threatening conditions while facing an unmet therapeutic need. Hence, we assessed the immunogenicity, efficacy, and tolerance of IFN-Kinoid (IFN-K), an anti-IFNα vaccination strategy, in a well-known mouse model of systemic autoimmunity with SjS-like features: MRL/MpJ-Faslpr/lpr (MRL/lpr) mice. Two cohorts (with ISA51 or SWE01 as adjuvants) of 26 female MRL/lpr were divided in parallel groups, "controls" (not treated, PBS and Keyhole Limpet Hemocyanin [KLH] groups) or "IFN-K" and followed up for 122 days. Eight-week-old mice received intra-muscular injections (days 0, 7, 28, 56 and 84) of PBS, KLH or IFN-K, emulsified in the appropriate adjuvant, and blood samples were serially collected. At sacrifice, surviving mice were euthanized and their organs were harvested for histopathological analysis (focus score in salivary/lacrimal glands) and IFN signature evaluation. SjS-like features were monitored. IFN-K induced a disease-modifying polyclonal anti-IFNα antibody response in all treated mice with high IFNα neutralization capacities, type 1 IFN signature's reduction and disease features' (ocular and oral sicca syndrome, neuropathy, focus score, glandular production of BAFF) improvement, as reflected by the decrease in Murine Sjögren's Syndrome Disease Activity Index (MuSSDAI) modelled on EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). No adverse effects were observed. We herein report on the strong efficacy of an innovative anti-IFNα vaccination strategy in a mouse model of SjS, paving the way for further clinical development (a phase IIb trial has just been completed in systemic lupus erythematosus with promising results)., Competing Interests: Authors FC, PH and GG-V were employed by company NEOVACS S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Killian, Colaone, Haumont, Nicco, Cerles, Chouzenoux, Cathébras, Rochereau, Chanut, Thomas, Laroche, Forest, Grouard-Vogel, Batteux and Paul.)
- Published
- 2021
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22. Immune cells and Notch1 signaling appear to drive the epithelial to mesenchymal transition in the development of adenomyosis in mice.
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Bourdon M, Santulli P, Doridot L, Jeljeli M, Chêne C, Chouzenoux S, Nicco C, Marcellin L, Chapron C, and Batteux F
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- Adenomyosis chemically induced, Adenomyosis immunology, Adenomyosis pathology, Animals, Animals, Newborn, Disease Models, Animal, Epithelial Cells immunology, Epithelial Cells pathology, Female, Gene Expression Regulation, Developmental, Mice, Signal Transduction, Tamoxifen, Time Factors, Uterus immunology, Uterus pathology, Adenomyosis metabolism, Epithelial Cells metabolism, Epithelial-Mesenchymal Transition, Receptor, Notch1 metabolism, Uterus metabolism
- Abstract
The epithelial to mesenchymal transition (EMT) has been implicated in the development of adenomyosis, along with dysregulated immune responses. Inflammation potentially induces Notch signaling, which could promote this EMT. The objective of this study was to investigate the involvement of immune cells and Notch1-mediated EMT in the development of adenomyosis. Adenomyosis was induced in 18 CD-1 mice by neonatal oral administration of tamoxifen (TAM group), while 18 neonates received vehicle only (Control group). Their uteri were sampled at 30, 60 or 90 days of age. Immune cell markers (Cd45, Ly6c1, Cd86, Arginine1, Cd19, Cd4, Cd8), Notch1 and its target genes (Hey1, Hey2, Hes1, Hes5) and biomarkers of EMT (E-Cadherin, Vimentin, Tgfb, Snail1, Slug, Snail3) were analyzed by quantitative RT-PCR and immunohistochemistry. Activated-Notch1 protein was measured by western blot. Aberrant expression of immune cell markers was observed in the uteri of mice as they developed adenomyosis. The expression of inflammatory cell markers, notably M1 macrophages and natural killer cells, was increased from Day 30 in the TAM group compared to controls, followed by an increase in the Cd4 marker (T cells) at Day 60. Conversely, expression of the Cd19 marker (B cells) was significantly reduced at all of the stages studied. Notch1 signaling was also highly activated compared to controls at Day 30 and Day 60. Concomitantly, the levels of several markers for EMT were also higher. Therefore, the activation of Notch1 coincides with aberrant expression of immune and EMT markers in the early development of adenomyosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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23. Prevention of esophageal stricture after circumferential endoscopic submucosal dissection using a modified self-assembling peptide.
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Oumrani S, Barret M, Beuvon F, Nicco C, Chêne C, Batteux F, and Prat F
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- Animals, Esophageal Mucosa, Peptides, Swine, Barrett Esophagus, Endoscopic Mucosal Resection adverse effects, Esophageal Neoplasms surgery, Esophageal Stenosis etiology, Esophageal Stenosis prevention & control
- Abstract
Circumferential endoscopic resection (ER) of the esophageal mucosa could find its place in the treatment of dysplastic Barrett's esophagus or extensive squamous cell neoplasia. However, the occurrence of esophageal strictures remains a major complication after ER exceeding 75% of the circumference. The aim of this study was to assess the effect of a modified, pH = 2, self-assembling peptide matrix (4[Arg-Ala-Asp-Ala]) (SAP) on the development of esophageal stricture after circumferential ER in a swine model. We performed a circumferential ER in 35 swine under general anesthesia. Five animals were included in the control group, 11 animals received the SAP matrix immediately after the resection, and 11 received the SAP matrix associated to a local steroid immediately after the resection. Follow-up endoscopy and esophagogram were performed before slaughter and necropsy at day 14. Eight treated animals were kept alive until day 28. At day 14, 27% of the animals in the SAP group developed a symptomatic stricture versus 100% in the control group (P = 0.008) and 50% in the SAP-triamcinolone group (P = 0.11). Application of an SAP matrix after circumferential ER in the swine allowed a significant reduction of the incidence of symptomatic stricture at day 14. Adding triamcinolone brought no significant improvement., (© The Author(s) 2021. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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24. LPS low -Macrophages Alleviate the Outcome of Graft- Versus -Host Disease Without Aggravating Lymphoma Growth in Mice.
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Jeljeli M, Chêne C, Chouzenoux S, Thomas M, Segain B, Doridot L, Nicco C, and Batteux F
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- Animals, Carcinogenesis, Cell Proliferation, Cells, Cultured, Cellular Reprogramming, Female, Immune Tolerance, Interleukin-10 metabolism, Lipopolysaccharides metabolism, Macrophages transplantation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Transplantation, Homologous, Graft vs Host Disease immunology, Hematopoietic Stem Cell Transplantation, Lymphoma immunology, Macrophages immunology, T-Lymphocytes immunology
- Abstract
Despite significant therapeutic advances, graft- versus -host disease (GvHD) remains the main life-threatening complication following allogeneic hematopoietic stem cell transplantation. The pathogenesis of GvHD is dominated by a dysregulated allogeneic immune response that drives fibrosis and autoimmunity in chronic forms. A multitude of cell therapy approaches, including infusion of myeloid cells, has been proposed to prevent GvHD through tolerance induction but yielded variable results. Myeloid cells like macrophages can be reprogrammed to develop adaptive-like features following antigenic challenge to reinforce or inhibit a subsequent immune response; a phenomenon termed 'trained immunity'. Here we report that, whereas LPS
low -trained macrophages elicit a suppressor effect on allogeneic T cell proliferation and function in vitro in an IL-10-dependent manner, Bacille Calmette et Guérin (BCG)-trained macrophages exert an opposite effect. In a murine model of sclerodermatous chronic GvHD, LPSlow -trained macrophages attenuate clinical signs of GvHD with significant effects on T cell phenotype and function, autoantibodies production, and tissue fibrosis. Furthermore, infusion of LPSlow -macrophages significantly improves survival in mice with acute GvHD. Importantly, we also provide evidence that LPSlow -macrophages do not accelerate A20-lymphoma tumor growth, which is significantly reduced upon transfer of BCG-macrophages. Collectively, these data indicate that macrophages can be trained to significantly inhibit in vitro and in vivo allo-reactive T cell proliferation without exhibiting pro-tumoral effect, thereby opening the way to promising clinical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jeljeli, Chêne, Chouzenoux, Thomas, Segain, Doridot, Nicco and Batteux.)- Published
- 2021
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25. Long-term exposure to monoclonal anti-TNF is associated with an increased risk of lymphoma in BAFF-transgenic mice.
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Nocturne G, Ly B, Paoletti A, Pascaud J, Seror R, Nicco C, Mackay F, Vincent FB, Lazure T, Ferlicot S, Stimmer L, Pascal Q, Roulland S, Krzysiek R, Hacein-Bey S, Batteux F, and Mariette X
- Subjects
- Animals, Autoimmune Diseases immunology, Autoimmunity immunology, B-Lymphocytes immunology, Cell Line, Mice, Mice, Inbred C57BL, Spleen immunology, Antibodies, Monoclonal immunology, Arthritis, Rheumatoid immunology, B-Cell Activating Factor immunology, Lymphoma immunology, Mice, Transgenic immunology, Tumor Necrosis Factor Inhibitors immunology, Tumor Necrosis Factor-alpha immunology
- Abstract
The impact of treatment on the risk of lymphoma in patients with rheumatoid arthritis (RA) is unclear. Here, we aimed to assess if the risk of lymphoma differs according to the type of tumor necrosis factor inhibitor (TNFi), comparing monoclonal anti-TNF antibodies to the soluble TNF receptor. We used B cell activating factor belonging to the TNF family (BAFF)-transgenic (Tg) mice as a model of autoimmunity-associated lymphoma. Six-month-old BAFF-Tg mice were treated with TNFi for 12 months. Histological examination of the spleen, assessment of the cellular composition of the spleen by flow cytometry and assessment of B cell clonality were performed at euthanasia. Crude mortality and incidence of lymphoma were significantly higher in mice treated with monoclonal anti-TNF antibodies compared to both controls and mice treated with the soluble TNF receptor, even at a high dose. Flow cytometry analysis revealed decreased splenic macrophage infiltration in mice treated with monoclonal anti-TNF antibodies. Overall, this study demonstrates, for the first time, that a very prolonged treatment with monoclonal anti-TNF antibodies increase the risk of lymphoma in B cell-driven autoimmunity. These data suggest a closer monitoring for lymphoma development in patients suffering from B cell-driven autoimmune disease with long-term exposure to monoclonal anti-TNF antibodies., (© 2021 British Society for Immunology.)
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- 2021
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26. Corrigendum: The Nrf2 -Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma.
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Kavian N, Mehlal S, Jeljeli M, Saidu NEB, Nicco C, Cerles O, Chouzenoux S, Cauvet A, Camus C, Ait-Djoudi M, Chéreau C, Kerdine-Römer S, Allanore Y, and Batteux F
- Abstract
[This corrects the article DOI: 10.3389/fimmu.2018.01896.]., (Copyright © 2021 Kavian, Mehlal, Jeljeli, Saidu, Nicco, Cerles, Chouzenoux, Cauvet, Camus, Ait-Djoudi, Chéreau, Kerdine-Römer, Allanore and Batteux.)
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- 2021
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27. Macrophage Immune Memory Controls Endometriosis in Mice and Humans.
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Jeljeli M, Riccio LGC, Chouzenoux S, Moresi F, Toullec L, Doridot L, Nicco C, Bourdon M, Marcellin L, Santulli P, Abrão MS, Chapron C, and Batteux F
- Subjects
- Adoptive Transfer, Animals, Coculture Techniques, Cytokines biosynthesis, Endometriosis microbiology, Female, Gram-Negative Bacterial Infections complications, Humans, Immune Tolerance, Lipopolysaccharides, Mice, Phenotype, Endometriosis immunology, Endometriosis pathology, Immunologic Memory, Macrophages, Peritoneal immunology
- Abstract
Endometriosis is a frequent, chronic, inflammatory gynecological disease characterized by the presence of ectopic endometrial tissue causing pain and infertility. Macrophages have a central role in lesion establishment and maintenance by driving chronic inflammation and tissue remodeling. Macrophages can be reprogrammed to acquire memory-like characteristics after antigenic challenge to reinforce or inhibit a subsequent immune response, a phenomenon termed "trained immunity." Here, whereas bacille Calmette-Guérin (BCG) training enhances the lesion growth in a mice model of endometriosis, tolerization with repeated low doses of lipopolysaccharide (LPS
low ) or adoptive transfer of LPSlow -tolerized macrophages elicits a suppressor effect. LPSlow -tolerized human macrophages mitigate the fibro-inflammatory phenotype of endometriotic cells in an interleukin-10 (IL-10)-dependent manner. A history of severe Gram-negative infection is associated with reduced infertility duration and alleviated symptoms, in contrast to patients with Gram-positive infection history. Thus, the manipulation of innate immune memory may be effective in dampening hyper-inflammatory conditions, opening the way to promising therapeutic approaches., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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28. Identification of TP53 mutated group using a molecular and immunohistochemical classification of endometrial carcinoma to improve prognostic evaluation for adjuvant treatments.
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Beinse G, Rance B, Just PA, Izac B, Letourneur F, Saidu NEB, Chouzenoux S, Nicco C, Goldwasser F, Batteux F, Durdux C, Chapron C, Pasmant E, Leroy K, Alexandre J, and Borghese B
- Subjects
- Adult, Aged, Aged, 80 and over, Chemotherapy, Adjuvant, DNA Polymerase II genetics, Decision Making, Female, Humans, Hysterectomy, Immunohistochemistry, Microsatellite Instability, Middle Aged, Mutation, Neoplasm Staging, Poly-ADP-Ribose Binding Proteins genetics, Prognosis, Proportional Hazards Models, Radiotherapy, Adjuvant, Endometrial Neoplasms genetics, Endometrial Neoplasms therapy, Tumor Suppressor Protein p53 genetics
- Abstract
Introduction: Molecular classification of endometrial carcinoma has been proposed to predict survival. However, its role in patient management remains to be determined. We aimed to identify whether a molecular and immunohistochemical classification of endometrial carcinoma could improve decision-making for adjuvant therapy., Methods: All consecutive patients treated for endometrial carcinoma between 2010 and 2017 at Cochin University Hospital were included. Clinical risk of relapse was based on European Society for Medical Oncology-European Society of Gynaecological Oncology-European SocieTy for Radiotherapy & Oncology (ESMO-ESGO-ESTRO) consensus. The clinical event of interest was event-free survival. Formalin-fixed paraffin-embedded tissue samples were processed for histopathological analysis and DNA extraction. The nuclear expression of mismatch repair and TP53 proteins was analyzed by immunohistochemistry. Next-generation sequencing of a panel of 15 genes including TP53 and POLE was performed using Ampliseq panels on Ion Torrent PGM (ThermoFisher). Tumors were allocated into four molecular groups using a sequential method based on next-generation sequencing and immunohistochemistry data: (1) POLE /ultramutated-like; (2) MSI/hypermutated-like (mismatch repair-deficient); (3) TP53 -mutated (without POLE mutations or mismatch repair deficiency); (4) not otherwise specified (the remaining tumors)., Results: 159 patients were included; 125 tumors were available for molecular characterization and distributed as follows: (1) POLE /ultramutated-like: n=4 (3%); (2) MSI/hypermutated-like: n=35 (30%); (3) TP53 -mutated: n=30 (25%); and (4) not otherwise specified: n=49 (42%). Assessing the TP53 status by immunohistochemistry only rather than next-generation sequencing would have misclassified 6 tumors (5%). TP53 -mutated tumors were associated with poor prognosis, independently of International Federation of Gynecology and Obstetrics (FIGO) stage and histological grade (Cox-based adjusted hazard ratio (aHR) 5.54, 95% CI 2.30 to 13.4), and independently of clinical risk of relapse (aHR 3.92, 95% CI 1.59 to 9.64). Among patients with FIGO stage I-II tumors, 6 (38%) TP53 -mutated tumors had low/intermediate clinical risk of relapse and did not receive adjuvant chemotherapy or radiotherapy., Conclusion: Endometrial carcinoma molecular classification identified potentially under-treated patients with poor molecular prognosis despite being at low/intermediate clinical risk of relapse. Consideration of molecular classification in adjuvant therapeutic decisions should be evaluated in prospective trials., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2020. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2020
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29. From Donor to Patient: Collection, Preparation and Cryopreservation of Fecal Samples for Fecal Microbiota Transplantation.
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Nicco C, Paule A, Konturek P, and Edeas M
- Abstract
Fecal Microbiota Transplantation (FMT) is suggested as an efficacious therapeutic strategy for restoring intestinal microbial balance, and thus for treating disease associated with alteration of gut microbiota. FMT consists of the administration of fresh or frozen fecal microorganisms from a healthy donor into the intestinal tract of diseased patients. At this time, in according to healthcare authorities, FMT is mainly used to treat recurrent Clostridium difficile . Despite the existence of a few existing stool banks worldwide and many studies of the FMT, there is no standard method for producing material for FMT, and there are a multitude of factors that can vary between the institutions. The main constraints for the therapeutic uses of FMT are safety concerns and acceptability. Technical and logistical issues arise when establishing such a non-standardized treatment into clinical practice with safety and proper governance. In this context, our manuscript describes a process of donor safety screening for FMT compiling clinical and biological examinations, questionnaires and interviews of donors. The potential risk of transmission of SARS-CoV-2 virus by the use of fecal microbiota for transplantation must be taken urgently into consideration. We discuss a standardized procedure of collection, preparation and cryopreservation of fecal samples through to the administration of material to patients, and explore the risks and limits of this method of FMT. The future success of medicine employing microbiota transplantation will be tightly related to its modulation and manipulation to combat dysbiosis. To achieve this goal, standard and strict methods need to be established before performing any type of FMT.
- Published
- 2020
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30. Ultrasound-induced Cavitation enhances the efficacy of Chemotherapy in a 3D Model of Pancreatic Ductal Adenocarcinoma with its microenvironment.
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Leenhardt R, Camus M, Mestas JL, Jeljeli M, Abou Ali E, Chouzenoux S, Bordacahar B, Nicco C, Batteux F, Lafon C, and Prat F
- Subjects
- Animals, Cell Line, Tumor, Deoxycytidine pharmacology, Mice, Mice, Transgenic, Spheroids, Cellular metabolism, Spheroids, Cellular pathology, Gemcitabine, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal therapy, Deoxycytidine analogs & derivatives, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Neoplasms, Experimental therapy, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Pancreatic Neoplasms therapy, Tumor Microenvironment drug effects, Ultrasonic Therapy
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is supported by a complex microenvironment whose physical contribution to chemoresistance could be overcome by ultrasound (US) therapy. This study aims to investigate the ability of US-induced inertial cavitation in association with chemotherapy to alter tumor cell viability via microenvironment disruption. For this purpose, we used a 3D-coculture PDAC model partially mimicking the tumor and its microenvironment. Coculture spheroids combining DT66066 cells isolated from KPC-transgenic mice and murine embryonic fibroblasts (iMEF) were obtained by using a magnetic nanoshuttle method. Spheroids were exposed to US with incremental inertial cavitation indexes. Conditions studied included control, gemcitabine, US-cavitation and US-cavitation + gemcitabine. Spheroid viability was assessed by the reduction of resazurin and flow cytometry. The 3D-coculture spheroid model incorporated activated fibroblasts and produced type 1-collagen, thus providing a partial miniature representation of tumors with their microenvironment. Main findings were: (a) Gemcitabine (5 μM) was significantly less cytotoxic in the presence of KPC/iMEFs spheroids compared with KPC (fibroblast-free) spheroids; (b) US-induced inertial cavitation combined with Gemcitabine significantly decreased spheroid viability compared to Gemcitabine alone; (c) both cavitation and chemotherapy affected KPC cell viability but not that of fibroblasts, confirming the protective role of the latter vis-à-vis tumor cells. Gemcitabine toxicity is enhanced when cocultured spheroids of KPC and iMEF are exposed to US-cavitation. Although the model used is only a partial representation of PDAC, this experience supports the hypothesis that US-inertial cavitation can enhance drug penetration and cytotoxicity by disrupting PDAC microenvironment.
- Published
- 2019
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31. Trained immunity modulates inflammation-induced fibrosis.
- Author
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Jeljeli M, Riccio LGC, Doridot L, Chêne C, Nicco C, Chouzenoux S, Deletang Q, Allanore Y, Kavian N, and Batteux F
- Subjects
- Adoptive Transfer, Animals, Cytokines genetics, Cytokines immunology, Female, Fibrosis genetics, Fibrosis therapy, Humans, Immunity, Mice, Mice, Inbred BALB C, Scleroderma, Systemic genetics, Scleroderma, Systemic therapy, Fibrosis immunology, Macrophages immunology, Scleroderma, Systemic immunology
- Abstract
Chronic inflammation and fibrosis can result from inappropriately activated immune responses that are mediated by macrophages. Macrophages can acquire memory-like characteristics in response to antigen exposure. Here, we show the effect of BCG or low-dose LPS stimulation on macrophage phenotype, cytokine production, chromatin and metabolic modifications. Low-dose LPS training alleviates fibrosis and inflammation in a mouse model of systemic sclerosis (SSc), whereas BCG-training exacerbates disease in this model. Adoptive transfer of low-dose LPS-trained or BCG-trained macrophages also has beneficial or harmful effects, respectively. Furthermore, coculture with low-dose LPS trained macrophages reduces the fibro-inflammatory profile of fibroblasts from mice and patients with SSc, indicating that trained immunity might be a phenomenon that can be targeted to treat SSc and other autoimmune and inflammatory fibrotic disorders.
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- 2019
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32. Oxaliplatin-induced neuropathy: the preventive effect of a new super-oxide dismutase modulator.
- Author
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Guillaumot MA, Cerles O, Bertrand HC, Benoit E, Nicco C, Chouzenoux S, Schmitt A, Batteux F, Policar C, and Coriat R
- Abstract
By using the differential in level of oxidative status between normal and cancer cells, SuperOxide Dismutase (SOD) mimetics can have anti-tumor efficacy and prevent oxaliplatin-induced peripheral neuropathy. Our objective was to evaluate the neuroprotective efficacy of MAG, a new SOD mimic. In vitro , the effects of MAG alone or with oxaliplatin were studied on colon cancer cells (HT29 and CT26) and on normal fibroblast cells (NIH3T3). The cell viability (by crystal violet) as well as the production of reactive forms of oxygen and glutathione (by spectrofluorimetric assay) was measured. In vivo , efficacy on tumor growth was assessed in mice grafted with CT26 colon cancer cells. The effects on induced neurotoxicity were measured by specific behavioral Von Frey nociception, cold-plate tests, specific functional neuromuscular assay and electron microscopy. In vitro , MAG induced a production of hydrogen peroxide in all cells. At 24 h-incubation, MAG exhibits a cytotoxic activity in all cell lines. A cytotoxic additive effect of MAG and oxaliplatin was observed through oxidative burst. In vivo , oxaliplatin-treated mice associated with MAG did not counteract oxaliplatin's antitumoral efficacy. After 4 weeks of treatment with oxaliplatin combined with MAG, behavioral and functional tests showed a decrease in peripheral neuropathy induced by oxaliplatin in vivo . Electron microscopy analyses on sciatic nerves revealed an oxaliplatin-induced demyelination which is prevented by the association of MAG to this chemotherapy. In conclusion, MAG prevents the appearance of sensitive axonal neuropathy and neuromuscular disorders induced by oxaliplatin without affecting its antitumor activity., Competing Interests: CONFLICTS OF INTEREST The author(s) received no specific funding for this work., (Copyright: © 2019 Guillaumot et al.)
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- 2019
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33. Cavitation-induced release of liposomal chemotherapy in orthotopic murine pancreatic cancer models: A feasibility study.
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Camus M, Vienne A, Mestas JL, Pratico C, Nicco C, Chereau C, Marie JM, Moussatov A, Renault G, Batteux F, Lafon C, and Prat F
- Subjects
- Animals, Disease Models, Animal, Doxorubicin administration & dosage, Drug Delivery Systems methods, Feasibility Studies, Female, Liposomes, Male, Mice, Mice, Nude, Polyethylene Glycols administration & dosage, Rats, Rats, Inbred Lew, Ultrasonography, Antibiotics, Antineoplastic administration & dosage, Doxorubicin analogs & derivatives, Pancreatic Neoplasms drug therapy
- Abstract
Targeted and triggered release of liposomal drug using ultrasound (US) induced cavitation represents a promising treatment modality to increase the therapeutic-toxicity ratio of encapsulated chemotherapy., Objectives: To study the feasibility and efficacy of a combination of focused US and liposomal doxorubicin (US-L-DOX) release in orthotopic murine models of pancreatic cancer., Material and Methods: A confocal US setup was developed to generate US inertial cavitation delivery in a controlled and reproducible manner and designed for two distinct murine orthotopic pancreatic cancer models. Controlled cavitation at 1 MHz was applied within the tumors after L-DOX injection according to a preliminary pharmacokinetic study., Results: In vitro studies confirmed that L-DOX was cytostatic. In vivo pharmacokinetic study showed L-DOX peak tumor accumulation at 48h. Feasibility of L-DOX injection and US delivery was demonstrated in both murine models. In a nude mouse model, at W9 after implantation (W5 after treatment), US-L-DOX group (median [IQR] 51.43 mm
3 [35.1-871.95]) exhibited significantly lower tumor volumes than the sham group (216.28 [96.12-1202.92]), the US group (359.44 [131.48-1649.25]), and the L-DOX group (255.94 [84.09-943.72]), and a trend, although not statistically significant, to a lower volume than Gemcitabine group (90.48 [42.14-367.78])., Conclusion: This study demonstrates that inertial cavitation can be generated to increase the therapeutic effect of drug-carrying liposomes accumulated in the tumor. This approach is potentially an important step towards a therapeutic application of cavitation-induced drug delivery in pancreatic cancer., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
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34. Dimethyl fumarate, a two-edged drug: Current status and future directions.
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Saidu NEB, Kavian N, Leroy K, Jacob C, Nicco C, Batteux F, and Alexandre J
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- Animals, Humans, Dermatologic Agents therapeutic use, Dimethyl Fumarate therapeutic use
- Abstract
Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing-remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine-rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose-dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2. Some other studies performed indicate also the potential role of DMF in cancers, which are dependent on the NRF2 antioxidant and cellular detoxification program, such as KRAS-mutated lung adenocarcinoma. It, however, seems that DMF has multiple biological effects as it has been shown to also inhibit the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus blocking downstream targets that may be involved in the development and progression of inflammatory cascades leading to various disease processes, including tumors, lymphomas, diabetic retinopathy, arthritis, and psoriasis. Herein, we present the current status and future directions of the use of DMF in various diseases models with particular emphases on its targeting of specific intracellular signal transduction cascades in cancer; to shed some light on its possible mode of action., (© 2019 Wiley Periodicals, Inc.)
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- 2019
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35. B lymphocytes inactivation by Ibrutinib limits endometriosis progression in mice.
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Riccio LGC, Jeljeli M, Santulli P, Chouzenoux S, Doridot L, Nicco C, Reis FM, Abrão MS, Chapron C, and Batteux F
- Subjects
- Adenine analogs & derivatives, Animals, Cytokines blood, Disease Progression, Drug Evaluation, Preclinical, Endometriosis blood, Endometriosis immunology, Female, Mice, Inbred BALB C, Piperidines, Pyrazoles pharmacology, Pyrimidines pharmacology, T-Lymphocytes drug effects, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, B-Lymphocytes drug effects, Endometriosis drug therapy, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Abstract
Study Question: What are the effects of B lymphocyte inactivation or depletion on the progression of endometriosis?, Summary Answer: Skewing activated B cells toward regulatory B cells (Bregs) by Bruton's tyrosine kinase (Btk) inhibition using Ibrutinib prevents endometriosis progression in mice while B cell depletion using an anti-CD20 antibody has no effect., What Is Known Already: A polyclonal activation of B cells and the presence of anti-endometrial autoantibodies have been described in a large proportion of women with endometriosis though their exact role in the disease mechanisms remains unclear., Study Design, Size, Duration: This study included comparison of endometriosis progression for 21 days in control mice versus animals treated with the anti-CD20 depleting antibody or with the Btk inhibitor Ibrutinib that prevents B cell activation., Participants/materials, Setting, Methods: After syngeneic endometrial transplantation, murine endometriotic lesions were compared between treated and control mice using volume, weight, ultrasonography, histology and target genes expression in lesions. Phenotyping of activated and regulatory B cells, T lymphocytes and macrophages was performed by flow cytometry on isolated spleen and peritoneal cells. Cytokines were assayed by ELISA., Main Results and the Role of Chance: Btk inhibitor Ibrutinib prevented lesion growth, reduced mRNA expression of cyclooxygenase-2, alpha smooth muscle actin and type I collagen in the lesions and skewed activated B cells toward Bregs in the spleen and peritoneal cavity of mice with endometriosis. In addition, the number of M2 macrophages decreased in the peritoneal cavity of Ibrutinib-treated mice compared to anti-CD20 and control mice. Depletion of B cells using an anti-CD20 antibody had no effect on activity and growth of endometriotic lesions and neither on the macrophages, compared to control mice., Large Scale Data: N/A., Limitations, Reasons for Caution: It is still unclear whether B cell depletion by the anti-CD20 or inactivation by Ibrutinib can prevent establishment and/or progression of endometriosis in humans., Wider Implications of the Findings: Further investigation may contribute to clarifying the role of B cell subsets in human endometriosis., Study Funding/competing Interest(s): This research was supported by a grant of Institut National de la Santé et de la Recherche Médicale and Paris Descartes University. None of the authors has any conflict of interest to disclose., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2019
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36. Role of thyroid dysimmunity and thyroid hormones in endometriosis.
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Peyneau M, Kavian N, Chouzenoux S, Nicco C, Jeljeli M, Toullec L, Reboul-Marty J, Chenevier-Gobeaux C, Reis FM, Santulli P, Doridot L, Chapron C, and Batteux F
- Subjects
- Animals, Cell Proliferation physiology, Endometrium metabolism, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Reactive Oxygen Species metabolism, Retrospective Studies, Thyrotropin metabolism, Thyroxine metabolism, Triiodothyronine metabolism, Endometriosis metabolism, Thyroid Gland metabolism, Thyroid Hormones metabolism
- Abstract
Endometriosis is characterized by the presence of ectopic endometrial cells outside the uterine cavity. Thyroid autoimmunity has been associated with endometriosis. This work investigated the potential pathophysiological link between endometriosis and thyroid disorders. Transcripts and proteins involved in thyroid metabolism are dysregulated in eutopic and ectopic endometrium of endometriotic patients, leading to resistance of ectopic endometrium to triiodothyronine (T3) action and local accumulation of thyroxine (T4). Thyroid-stimulating hormone (TSH) acts as a proliferative and prooxidative hormone on all endometria of endometriosis patients and controls, whereas T3 and T4 act to specifically increase ectopic endometrial cell proliferation and reactive oxygen species (ROS) production. Mouse studies confirmed the data gained in vitro since endometriotic implants were found to be bigger when thyroid hormones increased. A retrospective analysis of endometriosis patients with or without a thyroid disorder revealed an increased chronic pelvic pain and disease score in endometriotic patients with a thyroid disorder., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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37. The NRF2 transcriptional target NQO1 has low mRNA levels in TP53-mutated endometrial carcinomas.
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Beinse G, Just PA, Rance B, Izac B, Letourneur F, Saidu NEB, Chouzenoux S, Nicco C, Goldwasser F, Pasmant E, Batteux F, Borghese B, Alexandre J, and Leroy K
- Subjects
- Adult, Aged, Aged, 80 and over, Endometrial Neoplasms diagnosis, Endometrial Neoplasms pathology, Female, Gene Expression Regulation, Neoplastic, Humans, Kelch-Like ECH-Associated Protein 1 genetics, Middle Aged, NF-E2-Related Factor 2 genetics, Prognosis, RNA, Messenger genetics, Endometrial Neoplasms genetics, Mutation, NAD(P)H Dehydrogenase (Quinone) genetics, NF-E2-Related Factor 2 metabolism, Transcription, Genetic, Tumor Suppressor Protein p53 genetics
- Abstract
Background: NRF2 is a major transcription factor regulating the expression of antioxidative/detoxifying enzymes, involved in oncogenic processes and drug resistance. We aimed to identify molecular alterations associated with NRF2 activation in endometrial carcinoma (EC)., Methods: Ninety patients treated (2012-2017) for localized/locally advanced EC were included in this study. Formalin-fixed paraffin-embedded tissue samples were processed for immunohistochemical (NRF2 and Mismatch Repair proteins) analyses. Next generation sequencing (NGS) of a panel of genes including POLE, TP53, NFE2L2, KEAP1 and CUL3 was performed using Ampliseq panels on Ion Torrent PGM (ThermoFisher). NRF2 activity was assessed by NQO1, GCLC, and AKR1C3 mRNA expressions, using TaqMan assays and quantitative RT-PCR., Results: Tumors were classified as POLE exonuclease domain mutated (N = 3, 3%), MMR-deficient (MSI-like) (N = 28, 31%), TP53 mutated (Copy-number high-like) (N = 22, 24%), and other tumors (Copy-number low-like) (N = 32, 36%). NRF2 nuclear immunostaining did not correlate with NRF2 target genes expression. The 3 tumors with highest NRF2 target genes expression harbored oncogenic KEAP1 or NFE2L2 mutations. Low NQO1 mRNA and protein levels were observed in the TP53 mutated subgroup compared to others tumors (p < .05) and in silico analyses of The Cancer Genome Atlas data further indicated that NQO1 mRNA levels were lower in serous compared to endometrioid copy-number high EC., Conclusion: In contrast with previous reports based on immunohistochemistry, our study indicates that NRF2 activation is a rare event in EC, associated with NFE2L2 or KEAP1 mutations. The subset of aggressive EC with low NQO1 mRNA level might represent a specific subgroup, which could be sensitive to combination therapies targeting oxidative stress., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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38. Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth.
- Author
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Cerles O, Gonçalves TC, Chouzenoux S, Benoit E, Schmitt A, Bennett Saidu NE, Kavian N, Chéreau C, Gobeaux C, Weill B, Coriat R, Nicco C, and Batteux F
- Subjects
- Animals, Cell Line, Tumor, Diabetic Nephropathies chemically induced, Diabetic Nephropathies physiopathology, Diabetic Nephropathies prevention & control, Disease Models, Animal, Ganglia, Spinal drug effects, Ganglia, Spinal physiopathology, Hyperalgesia chemically induced, Hyperalgesia prevention & control, Male, Mice, Inbred BALB C, Oxaliplatin adverse effects, Peripheral Nervous System Diseases physiopathology, Sciatic Nerve drug effects, Sciatic Nerve physiopathology, Sensory Receptor Cells drug effects, Sensory Receptor Cells physiology, Antineoplastic Agents administration & dosage, Benztropine administration & dosage, Oxaliplatin administration & dosage, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases prevention & control
- Abstract
The endogenous cholinergic system plays a key role in neuronal cells, by suppressing neurite outgrowth and myelination and, in some cancer cells, favoring tumor growth. Platinum compounds are widely used as part of first line conventional cancer chemotherapy; their efficacy is however limited by peripheral neuropathy as a major side-effect. In a multiple sclerosis mouse model, benztropine, that also acts as an anti-histamine and a dopamine re-uptake inhibitor, induced the differentiation of oligodendrocytes through M1 and M3 muscarinic receptors and enhanced re-myelination. We have evaluated whether benztropine can increase anti-tumoral efficacy of oxaliplatin, while preventing its neurotoxicity.We showed that benztropine improves acute and chronic clinical symptoms of oxaliplatin-induced peripheral neuropathies in mice. Sensory alterations detected by electrophysiology in oxaliplatin-treated mice were consistent with a decreased nerve conduction velocity and membrane hyperexcitability due to alterations in the density and/or functioning of both sodium and potassium channels, confirmed by action potential analysis from ex-vivo cultures of mouse dorsal root ganglion sensory neurons using whole-cell patch-clamp. These alterations were all prevented by benztropine. In oxaliplatin-treated mice, MBP expression, confocal and electronic microscopy of the sciatic nerves revealed a demyelination and confirmed the alteration of the myelinated axons morphology when compared to animals injected with oxaliplatin plus benztropine. Benztropine also prevented the decrease in neuronal density in the paws of mice injected with oxaliplatin. The neuroprotection conferred by benztropine against chemotherapeutic drugs was associated with a lower expression of inflammatory cytokines and extended to diabetic-induced peripheral neuropathy in mice.Mice receiving benztropine alone presented a lower tumor growth when compared to untreated animals and synergized the anti-tumoral effect of oxaliplatin, a phenomenon explained at least in part by benztropine-induced ROS imbalance in tumor cells.This report shows that blocking muscarinic receptors with benztropine prevents peripheral neuropathies and increases the therapeutic index of oxaliplatin. These results can be rapidly transposable to patients as benztropine is currently indicated in Parkinson's disease in the United States.
- Published
- 2019
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39. Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis.
- Author
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Günther S, Bordenave J, Hua-Huy T, Nicco C, Cumont A, Thuillet R, Tu L, Quatremarre T, Guilbert T, Jalce G, Batteux F, Humbert M, Savale L, Guignabert C, and Dinh-Xuan AT
- Subjects
- Animals, Antigens, Differentiation, B-Lymphocyte genetics, Bleomycin toxicity, Disease Models, Animal, Female, Histocompatibility Antigens Class II genetics, Humans, Hypertension, Pulmonary chemically induced, Hypertension, Pulmonary genetics, Hypertension, Pulmonary pathology, Idiopathic Pulmonary Fibrosis chemically induced, Idiopathic Pulmonary Fibrosis genetics, Idiopathic Pulmonary Fibrosis pathology, Inflammation chemically induced, Inflammation genetics, Inflammation pathology, Isoxazoles administration & dosage, Lung drug effects, Lung metabolism, Lung pathology, Male, Mice, Receptors, CXCR4 genetics, Vascular Remodeling drug effects, Vascular Remodeling genetics, Hypertension, Pulmonary drug therapy, Idiopathic Pulmonary Fibrosis drug therapy, Inflammation drug therapy, Intramolecular Oxidoreductases genetics, Macrophage Migration-Inhibitory Factors genetics
- Abstract
Background: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that significantly contributes to morbidity and mortality. Macrophage migration inhibitory factor (MIF) is a critical factor in vascular remodeling of the pulmonary circulation., Objectives: We tested the effects of two small molecules targeting MIF on bleomycin (BLM)-induced collagen deposition, PH, and vascular remodeling in mouse lungs., Methods: We examined the distribution pattern of MIF, CD74, and CXCR4 in the lungs of patients with IPF-PH and the lungs of BLM-injected mice. Then, treatments were realized with ( S , R )-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and N -(3-hydroxy-4-fluorobenzyl)-5 trifluoromethylbenzoxazol-2-thione 31 (20 mg/kg/day per os for 3 weeks) started 24 h after an intratracheal BLM administration., Results: More intense immunoreactivity was noted for MIF, CD74, and CXCR4 in lungs from IPF-PH patients and BLM-injected mice. Furthermore, we found that treatments of BLM-injected mice with ISO-1 or compound 31 attenuated lung collagen deposition and right ventricular systolic pressure increase. Additionally, reduced pulmonary inflammatory infiltration and pulmonary arterial muscularization were observed in the lungs of BLM-injected mice treated with ISO-1 or compound 31 ., Conclusions: Treatments with ISO-1 or compound 31 attenuates BLM-induced inflammation and fibrosis in lung, and prevents PH development in mice, suggesting that MIF is an important factor for IPF-PH development.
- Published
- 2018
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40. T-cell costimulation blockade is effective in experimental digestive and lung tissue fibrosis.
- Author
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Boleto G, Guignabert C, Pezet S, Cauvet A, Sadoine J, Tu L, Nicco C, Gobeaux C, Batteux F, Allanore Y, and Avouac J
- Subjects
- Animals, Disease Models, Animal, Female, Fibrosis prevention & control, Humans, Hypertension, Pulmonary pathology, Hypertension, Pulmonary prevention & control, Immunosuppressive Agents pharmacology, Intestines pathology, Lung drug effects, Lung pathology, Lung Diseases, Interstitial pathology, Lung Diseases, Interstitial prevention & control, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, T-Lymphocytes immunology, T-Lymphocytes metabolism, Abatacept pharmacology, Intestines drug effects, Pulmonary Fibrosis prevention & control, T-Lymphocytes drug effects
- Abstract
Background: We aimed to investigate the efficacy of abatacept in preclinical mouse models of digestive involvement, pulmonary fibrosis, and related pulmonary hypertension (PH), mimicking internal organ involvement in systemic sclerosis (SSc)., Methods: Abatacept has been evaluated in the chronic graft-versus-host disease (cGvHD) mouse model (abatacept 1 mg/mL for 6 weeks), characterized by liver and intestinal fibrosis and in the Fra-2 mouse model (1 mg/mL or 10 mg/mL for 4 weeks), characterized by interstitial lung disease (ILD) and pulmonary vascular remodeling leading to PH., Results: In the cGvHD model, abatacept significantly decreased liver transaminase levels and markedly improved colon inflammation. In the Fra-2 model, abatacept alleviated ILD, with a significant reduction in lung density on chest microcomputed tomography (CT), fibrosis histological score, and lung biochemical markers. Moreover, abatacept reversed PH in Fra-2 mice by improving vessel remodeling and related cardiac hemodynamic impairment. Abatacept significantly reduced fibrogenic marker levels, T-cell proliferation, and M1/M2 macrophage infiltration in lesional lungs of Fra-2 mice., Conclusion: Abatacept improves digestive involvement, prevents lung fibrosis, and attenuates PH. These findings suggest that abatacept might be an appealing therapeutic approach beyond skin fibrosis for organ involvement in SSc.
- Published
- 2018
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41. The Nrf2 -Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma.
- Author
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Kavian N, Mehlal S, Jeljeli M, Saidu NEB, Nicco C, Cerles O, Chouzenoux S, Cauvet A, Camus C, Ait-Djoudi M, Chéreau C, Kerdine-Römer S, Allanore Y, and Batteux F
- Subjects
- Adolescent, Adult, Aged, Animals, Case-Control Studies, Cytokines metabolism, Disease Models, Animal, Endothelial Cells metabolism, Female, Fibroblasts metabolism, Fibrosis, Glutathione metabolism, Humans, Hydrogen Peroxide metabolism, Inflammation Mediators metabolism, Male, Mice, Middle Aged, Oxidation-Reduction, Oxidative Stress, Reactive Oxygen Species metabolism, Scleroderma, Systemic pathology, Scleroderma, Systemic therapy, Young Adult, Antioxidant Response Elements, Autoimmunity, NF-E2-Related Factor 2 metabolism, Scleroderma, Systemic etiology, Scleroderma, Systemic metabolism, Signal Transduction
- Abstract
Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and internal organs and vascular alterations. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of the disease. Indeed, reactive oxygen species (ROS) trigger neoepitopes leading to a breach of immune tolerance and autoimmune responses, activate fibroblasts to proliferate and to produce excess of type I collagen. ROS also alter endothelial cells leading to vascular dysfunction. Glutathione (GSH) is the most potent antioxidant system in eukaryotic cells. Numerous studies have reported a defect in GSH in SSc animal models and humans, but the origin of this defect remains unknown. The transcription factor NRF2 is a key player in the antioxidant defense, as it can induce the transcription of antioxidant and cytoprotective genes, including GSH, through its interaction with the antioxidant response elements. In this work, we investigated whether NRF2 could be implicated in the pathogenesis of SSc, and if this pathway could represent a new therapeutic target in this orphan disease with no curative medicine. Skin biopsies from 11 patients and 10 controls were harvested, and skin fibroblasts were extracted. Experimental SSc was induced both in BALB/c and in nrf2 mice by daily intradermal injections of hypochloric acid. In addition, diseased BALB/c mice were treated with an
-/- mice by daily intradermal injections of hypochloric acid. In addition, diseased BALB/c mice were treated with an nrf2 agonist, dimethyl fumarate, or placebo. A drop in nrf2 and target genes mRNA levels was observed in skin fibroblasts of SSc patients compared to controls. Moreover, the nrf2 pathway is also downregulated in skins and lungs of SSc mice. In addition, we observed that nrf2-/- mice have a more severe form of SSc with increased fibrosis and inflammation compared to wild-type SSc mice. Diseased mice treated with the nrf2 agonist dimethyl fumarate (DMF) exhibited reduced fibrosis and immune activation compared to untreated mice. The ex vivo treatment of skin fibroblasts from SSc mice with DMF restores GSH intracellular content, decreases ROS production and cell proliferation. These results suggest that the nrf2 pathway is highly dysregulated in human and SSc mice with deleterious consequences on fibrosis and inflammation and that Nrf2 modulation represents a therapeutic target in SSc.- Published
- 2018
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42. Dimethyl fumarate is highly cytotoxic in KRAS mutated cancer cells but spares non-tumorigenic cells.
- Author
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Bennett Saidu NE, Bretagne M, Mansuet AL, Just PA, Leroy K, Cerles O, Chouzenoux S, Nicco C, Damotte D, Alifano M, Borghese B, Goldwasser F, Batteux F, and Alexandre J
- Abstract
KRAS mutation, one of the most common molecular alterations observed in adult carcinomas, was reported to activate the anti-oxidant program driven by the transcription factor NRF2 (Nuclear factor-erythroid 2-related factor 2). We previously observed that the antitumoral effect of Dimethyl fumarate (DMF) is dependent of NRF2 pathway inhibition. We used in vitro methods to examine the effect of DMF on cell death and the activation of the NRF2/DJ-1 antioxidant pathway. We report here that DMF is preferentially cytotoxic against KRAS mutated cancer cells. This effect was observed in patient-derived cancer cell lines harbouring a G12V KRAS mutation, compared with cell lines without such a mutation. In addition, KRAS*G12V over-expression in the human Caco-2 colon cancer cell line significantly promoted DMF-induced cell death, as well as DMF-induced- reactive oxygen species (ROS) formation and -glutathione (GSH) depletion. Moreover, in contrast to malignant cells, our data confirms that the same concentration of DMF has no significant cytotoxic effects on non-tumorigenic human ARPE-19 retinal epithelial, murine 3T3 fibroblasts and primary mice bone marrow cells; but is rather associated with NRF2 activation, decreased ROS and increased GSH levels. Furthermore, DJ-1 down-regulation experiments showed that this protein does not play a protective role against NRF2 in non-tumorigenic cells, as it does in malignant ones. This, interestingly, could be at the root of the differential effect of DMF observed between malignant and non-tumorigenic cells. Our results suggest for the first time that the dependence on NRF2 observed in mutated KRAS malignant cells makes them more sensitive to the cytotoxic effect of DMF, which thus opens up new prospects for the therapeutic applications of DMF., Competing Interests: CONFLICTS OF INTEREST F. Goldwasser acted as a consultant on the Advisory Board for Fresenius Kabi. J Alexandre acted as a consultant on the Advisory Board for Novartis, Roche, Ipsen. K Leroy acted as a consultant on an Advisory Board for Roche. The other authors have no conflicts of interest to declare.
- Published
- 2018
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43. Microbiota Quality and Mitochondrial Activity Link with Occurrence of Muscle Cramps in Hemodialysis Patients using Citrate Dialysate: A Pilot Study.
- Author
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Durand PY, Nicco C, Serteyn D, Attaf D, and Edeas M
- Subjects
- Aged, Aged, 80 and over, Dysbiosis blood, Dysbiosis microbiology, Dysbiosis therapy, Female, Humans, Male, Mitochondria, Muscle pathology, Muscle Cramp, Pilot Projects, Bacteria classification, Bacteria growth & development, Citric Acid blood, Gastrointestinal Microbiome, Kidney Failure, Chronic blood, Kidney Failure, Chronic microbiology, Kidney Failure, Chronic therapy, Mitochondria, Muscle metabolism, Renal Dialysis
- Abstract
Background/aims: Hemodialysis-associated muscle cramp (HAMC) is a common complication under citrate dialysate (CD) occurring in 30% of cases. Our objectives were to assess the gut microbiota quality, mitochondrial activity, and to investigate their possible relationship with HAMC., Methods: Ten end-stage renal disease patients (78.9 ± 2.1 years) treated by hemodialysis (HD) with CD were enrolled and then classified according to the frequency of HAMCs: "frequent HAMCs group" (n = 5) and "absence of HAMCs group" (n = 5). Gut microbiota quality, mitochondrial activity, and some markers of oxidative stress (OS) were investigated., Results: In patients with cramps, gut microbiota diversity seemed lower and some genera including Helicobacter, Lachnospira, Roseburia, and Haemophilus seemed over-expressed, a significant increase of citratemia and significant lowering mitochondrial function were observed. No difference was observed on the OS markers., Conclusion: This first clinical study revealed a possible dysbiosis of microbiota and a mitochondrial dysfunction into HD patients with cramps under CD compared to patients without cramp., (© 2018 S. Karger AG, Basel.)
- Published
- 2018
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44. ROS Modulator Molecules with Therapeutic Potential in Cancers Treatments.
- Author
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Nicco C and Batteux F
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antioxidants chemistry, Antioxidants pharmacology, Antioxidants therapeutic use, Biological Products chemistry, Biological Products pharmacology, Biological Products therapeutic use, Catalysis, Drug Synergism, Humans, Neoplasms metabolism, Oxidation-Reduction, Plant Extracts chemistry, Plant Extracts pharmacology, Plant Extracts therapeutic use, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Reactive Oxygen Species metabolism, Superoxide Dismutase metabolism
- Abstract
Reactive Oxygen Species (ROS) are chemically reactive chemical species containing oxygen. The redox status of a cell is function of the relative concentrations of oxidized and reduced forms of proteins, enzymes, ROS, molecules containing thiol and other factors. In the organism, the redox balance is based on the generation and elimination of ROS produced by endogenous and exogenous sources. All living organisms must maintain their redox equilibrium to survive and proliferate. Enzymatic and molecular pathways control ROS levels tightly but differentially depending on the type of cell. This review is an overview of various molecules that modulate ROS production/detoxification and have a synergistic action with the chemotherapies to kill cancer cells while preserving normal cells to avoid anticancer drugs side effects, allowing a better therapeutic index of the anticancer treatments., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
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45. Alteration of Nrf2 and Glutamate Cysteine Ligase expression contribute to lesions growth and fibrogenesis in ectopic endometriosis.
- Author
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Marcellin L, Santulli P, Chouzenoux S, Cerles O, Nicco C, Dousset B, Pallardy M, Kerdine-Römer S, Just PA, Chapron C, and Batteux F
- Subjects
- Adult, Animals, Case-Control Studies, Choristoma metabolism, Choristoma pathology, Disease Models, Animal, Endometriosis metabolism, Endometriosis pathology, Endometrium pathology, Epithelial Cells metabolism, Epithelial Cells pathology, Female, Fibrosis, Gene Expression Regulation, Glutamate-Cysteine Ligase metabolism, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2 deficiency, NF-E2-Related Factor 2 metabolism, Oxidative Stress, Primary Cell Culture, Prospective Studies, Stromal Cells metabolism, Stromal Cells pathology, Tertiary Care Centers, Choristoma genetics, Endometriosis genetics, Endometrium metabolism, Glutamate-Cysteine Ligase genetics, NF-E2-Related Factor 2 genetics
- Abstract
The redox-sensitive nuclear factor erythroid-derived 2-like 2 (NRF2) controls endogenous antioxidant enzymes' transcription and protects against oxidative damage which is triggered by inflammation and known to favor progression of endometriosis. Glutamate Cysteine Ligase (GCL), a target gene of NRF2, is the first enzyme in the synthesis cascade of glutathione, an important endogenous antioxidant. Sixty-one patients, with thorough surgical examination of the abdominopelvic cavity, were recruited for the study: 31 with histologically-proven endometriosis and 30 disease-free women taken as controls. Expressions of NRF2 and GCL were investigated by quantitative RT-PCR and immunohistochemistry in eutopic and ectopic endometria from endometriosis-affected women and in endometrium of disease-free women. Ex vivo stromal and epithelial cells were extracted and purified from endometrial and endometriotic biopsies to explore expression of NRF2 and GCL in both stromal and epithelial compartments by western blot. Finally, in order to strengthen the role of NRF2 in endometriosis pathogenesis, we evaluated the drop of NRF2 expression in a mouse model of endometriosis using NRF2 knockout (NRF2
-/- ) mice. The mRNA levels of NRF2 and GCL were significantly lower in ectopic endometria of endometriosis-affected women compared to eutopic endometria of disease-free women. The immunohistochemical analysis confirmed the decreased expression of both NRF2 and GCL in ectopic endometriotic tissues compared to eutopic endometria of endometriosis-affected and disease-free women. Immunoblotting revealed a significant decreased of NRF2 and GCL expression in epithelial and stroma cells from ectopic lesions of endometriosis-affected women compared to eutopic endometria from controls. Using a murine model of endometriosis, NRF2-/- implants were more fibrotic compared to wild-type with an increased weight and volume. These findings indicate that expression of the transcription factor NRF2 and its effector GCL are both profoundly deregulated in endometriotic lesions towards increased growth and fibrogenetic processes., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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46. ADAM9 expression promotes an aggressive lung adenocarcinoma phenotype.
- Author
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Kossmann CM, Annereau M, Thomas-Schoemann A, Nicco-Overney C, Chéreau C, Batteux F, Alexandre J, and Lemare F
- Subjects
- A549 Cells, ADAM Proteins biosynthesis, Adenocarcinoma pathology, Adenocarcinoma of Lung, Animals, Biomarkers, Tumor biosynthesis, Cell Movement genetics, Cell Proliferation genetics, Gene Expression Regulation, Neoplastic, Heterografts, Humans, Lung Neoplasms pathology, Membrane Proteins biosynthesis, Mice, Neovascularization, Pathologic pathology, Receptors, Interleukin-8B genetics, ADAM Proteins genetics, Adenocarcinoma genetics, Biomarkers, Tumor genetics, Lung Neoplasms genetics, Membrane Proteins genetics, Neovascularization, Pathologic genetics
- Abstract
A disintegrin and metalloproteinase 9 (ADAM9) possesses potent metastasis-inducing capacities and is highly expressed in several cancer cells. Previous work has shown that ADAM9 participates in the adhesive-invasive phenotype in lung cancer cells in vitro. In this study, we evaluated whether ADAM9 expression plays a critical role in metastatic processes in vivo and in angiogenesis. We first found that high ADAM9 expression was correlated with poor lung adenocarcinoma patient prognosis on Prognoscan data base. In vivo model based on intravenous injection in nude mice showed that a stable downregulation of ADAM9 in A549 (TrA549 A9-) cells was associated with a lower number of nodules in the lung, suggesting lower potentials for extravasation and metastasis. On a subcutaneous xenograft we showed that TrA549 A9- produced significantly smaller tumours and exhibited fewer neovessels. In addition, in vitro human umbilical vein endothelial cells exposed to supernatant from TrA549 A9- could reduce the formation of more vessel-like structures. To further understand the mechanism, a human antibody array analysis confirmed that five cytokines were downregulated in TrA549 A9- cells. Interleukin 8 was the most significantly downregulated, and its interaction with CXCR2 was implicated in angiogenesis on an in vitro model. These results emphasize the critical influence of ADAM9 on lung cancer progression and aggressiveness. ADAM9 should at least be a marker of cancer aggressiveness and a potential therapeutic target for cancer treatment.
- Published
- 2017
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- View/download PDF
47. Leflunomide prevents ROS-induced systemic fibrosis in mice.
- Author
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Morin F, Kavian N, Chouzenoux S, Cerles O, Nicco C, Chéreau C, and Batteux F
- Subjects
- Animals, Autoantibodies blood, Bleomycin administration & dosage, Cells, Cultured, Disease Models, Animal, Female, Fibrosis, Humans, Hypochlorous Acid administration & dosage, Immunosuppression Therapy, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Leflunomide, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Pulmonary Fibrosis chemically induced, Reactive Oxygen Species metabolism, STAT6 Transcription Factor metabolism, Signal Transduction, Skin metabolism, Antirheumatic Agents therapeutic use, Isoxazoles therapeutic use, Macrophages immunology, Pulmonary Fibrosis drug therapy, Skin pathology
- Abstract
Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vasculopathy and immunological abnormalities. Recent insights into the polarization of macrophages in scleroderma and into the implication of STAT6 and KLF4 in this process have prompted us to investigate the effects of the inhibition of STAT6 signaling pathway by leflunomide in mice. SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl) or bleomycin. Mice were treated (or not) every other day, for 4 or 6 weeks, by leflunomide. Skin and lung fibrosis as well as immunological features were studied. Mice exposed to HOCl developed a diffuse cutaneous SSc with pulmonary fibrosis and anti-DNA topoisomerase 1 auto-antibodies. STAT6 pathway was hyperactivated and KLF4 was overexpressed in the skin and the lungs of diseased mice. Their inhibition by leflunomide prevented skin and lung fibrosis. Moreover, the hyperproliferative and pro-oxidative phenotype of skin and lung fibroblasts was reversed by leflunomide. Beneficial immunological effects of leflunomide were associated with decreased activation of CD4+ and CD8+ T cells, B cell activation, decreased auto-antibodies production and restored polarization of macrophages in the spleen. The improvement provided by leflunomide in both mouse models of SSc provides a rationale for the evaluation of this immunomodulating drug in the management of patients affected by this disease., (Copyright © 2017. Published by Elsevier Inc.)
- Published
- 2017
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48. Dimethyl Fumarate Controls the NRF2/DJ-1 Axis in Cancer Cells: Therapeutic Applications.
- Author
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Saidu NE, Noé G, Cerles O, Cabel L, Kavian-Tessler N, Chouzenoux S, Bahuaud M, Chéreau C, Nicco C, Leroy K, Borghese B, Goldwasser F, Batteux F, and Alexandre J
- Subjects
- Animals, Cell Line, Tumor, Cell Survival drug effects, Disease Models, Animal, Female, Glutathione metabolism, Humans, Mice, Neoplasms drug therapy, Neoplasms pathology, Oxidative Stress drug effects, Reactive Oxygen Species metabolism, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Dimethyl Fumarate pharmacology, NF-E2-Related Factor 2 metabolism, Neoplasms metabolism, Protein Deglycase DJ-1 metabolism, Signal Transduction drug effects
- Abstract
The transcription factor NRF2 (NFE2L2), regulates important antioxidant and cytoprotective genes. It enhances cancer cell proliferation and promotes chemoresistance in several cancers. Dimethyl fumarate (DMF) is known to promote NRF2 activity in noncancer models. We combined in vitro and in vivo methods to examine the effect of DMF on cancer cell death and the activation of the NRF2 antioxidant pathway. We demonstrated that at lower concentrations (<25 μmol/L), DMF has a cytoprotective role through activation of the NRF2 antioxidant pathway. At higher concentrations, however (>25 μmol/L), DMF caused oxidative stress and subsequently cytotoxicity in several cancer cell lines. High DMF concentration decreases nuclear translocation of NRF2 and production of its downstream targets. The pro-oxidative and cytotoxic effects of high concentration of DMF were abrogated by overexpression of NRF2 in OVCAR3 cells, suggesting that DMF cytotoxicity is dependent of NRF2 depletion. High concentrations of DMF decreased the expression of DJ-1, a NRF2 protein stabilizer. Using DJ-1 siRNA and expression vector, we observed that the expression level of DJ-1 controls NRF2 activation, antioxidant defenses, and cell death in OVCAR3 cells. Finally, antitumoral effect of daily DMF (20 mg/kg) was also observed in vivo in two mice models of colon cancer. Taken together, these findings implicate the effect of DJ-1 on NRF2 in cancer development and identify DMF as a dose-dependent modulator of both NRF2 and DJ-1, which may be useful in exploiting the therapeutic potential of these endogenous antioxidants. Mol Cancer Ther; 16(3); 529-39. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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49. Niclosamide Inhibits Oxaliplatin Neurotoxicity while Improving Colorectal Cancer Therapeutic Response.
- Author
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Cerles O, Benoit E, Chéreau C, Chouzenoux S, Morin F, Guillaumot MA, Coriat R, Kavian N, Loussier T, Santulli P, Marcellin L, Saidu NE, Weill B, Batteux F, and Nicco C
- Subjects
- Animals, Cell Line, Tumor, Cell Survival drug effects, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Disease Models, Animal, Glutathione metabolism, Humans, Mice, Motor Neurons drug effects, Organoplatinum Compounds toxicity, Oxaliplatin, Oxidation-Reduction drug effects, Reactive Oxygen Species metabolism, Sensory Receptor Cells drug effects, Touch drug effects, Tumor Burden drug effects, Antineoplastic Agents pharmacology, Colorectal Neoplasms metabolism, Neuroprotective Agents pharmacology, Niclosamide pharmacology, Organoplatinum Compounds pharmacology
- Abstract
Neuropathic pain is a limiting factor of platinum-based chemotherapies. We sought to investigate the neuroprotective potential of niclosamide in peripheral neuropathies induced by oxaliplatin. Normal neuron-like and cancer cells were treated in vitro with oxaliplatin associated or not with an inhibitor of STAT3 and NF-κB, niclosamide. Cell production of reactive oxygen species and viability were measured by 2',7'-dichlorodihydrofluorescein diacetate and crystal violet. Peripheral neuropathies were induced in mice by oxaliplatin with or without niclosamide. Neurologic functions were assessed by behavioral and electrophysiologic tests, intraepidermal innervation, and myelination by immunohistochemical, histologic, and morphologic studies using confocal microscopy. Efficacy on tumor growth was assessed in mice grafted with CT26 colon cancer cells. In neuron-like cells, niclosamide downregulated the production of oxaliplatin-mediated H
2 O2 , thereby preventing cell death. In colon cancer cells, niclosamide enhanced oxaliplatin-mediated cell death through increased H2 O2 production. These observations were explained by inherent lower basal levels of GSH in cancer cells compared with normal and neuron-like cells. In neuropathic mice, niclosamide prevented tactile hypoesthesia and thermal hyperalgesia and abrogated membrane hyperexcitability. The teniacide also prevented intraepidermal nerve fiber density reduction and demyelination in oxaliplatin mice in this mixed form of peripheral neuropathy. Niclosamide prevents oxaliplatin-induced increased levels of IL6, TNFα, and advanced oxidized protein products. Niclosamide displayed antitumor effects while not abrogating oxaliplatin efficacy. These results indicate that niclosamide exerts its neuroprotection both in vitro and in vivo by limiting oxaliplatin-induced oxidative stress and neuroinflammation. These findings identify niclosamide as a promising therapeutic adjunct to oxaliplatin chemotherapy. Mol Cancer Ther; 16(2); 300-11. ©2016 AACR., (©2016 American Association for Cancer Research.)- Published
- 2017
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50. The Effects of Allicin, a Reactive Sulfur Species from Garlic, on a Selection of Mammalian Cell Lines.
- Author
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Gruhlke MC, Nicco C, Batteux F, and Slusarenko AJ
- Abstract
Garlic ( Allium sativum L.) has been used as a spice and medicinal plant since ancient times. Garlic produces the thiol-reactive defence substance, allicin, upon wounding. The effects of allicin on human lung epithelium carcinoma (A549), mouse fibroblast (3T3), human umbilical vein endothelial cell (HUVEC), human colon carcinoma (HT29) and human breast cancer (MCF7) cell lines were tested. To estimate toxic effects of allicin, we used a standard MTT-test (methylthiazoltetrazolium) for cell viability and ³H-thymidine incorporation for cell proliferation. The glutathione pool was measured using monobromobimane and the formation of reactive species was identified using 2',7'-dichlorofluoresceine-diacetate. The YO-PRO-1 iodide staining procedure was used to estimate apoptosis. Allicin reduced cell viability and cell proliferation in a concentration dependent manner. In the bimane test, it was observed that cells treated with allicin showed reduced fluorescence, suggesting glutathione oxidation. The cell lines tested differed in sensitivity to allicin in regard to viability, cell proliferation and glutathione oxidation. The 3T3 and MCF-7 cells showed a higher proportion of apoptosis compared to the other cell types. These data show that mammalian cell lines differ in their sensitivity and responses to allicin.
- Published
- 2016
- Full Text
- View/download PDF
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