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1. Long-term intake of Lactobacillus helveticus enhances bioavailability of omega-3 fatty acids in the mouse retina

Author

Pierre Lapaquette, Sébastien Terrat, Lil Proukhnitzky, Lucy Martine, Stéphane Grégoire, Bénédicte Buteau, Stéphanie Cabaret, Aurélie Rieu, Luis G. Bermúdez-Humarán, Pierre-Henry Gabrielle, Catherine Creuzot-Garcher, Olivier Berdeaux, Niyazi Acar, and Marie-Agnès Bringer

Subjects
Microbial ecology, QR100-130
Abstract

Abstract Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), are required for the structure and function of the retina. Several observational studies indicate that consumption of a diet with relatively high levels of n-3 PUFAs, such as those provided by fish oils, has a protective effect against the development of age-related macular degeneration. Given the accumulating evidence showing the role of gut microbiota in regulating retinal physiology and host lipid metabolism, we evaluated the potential of long-term dietary supplementation with the Gram-positive bacterium Lactobacillus helveticus strain VEL12193 to modulate the retinal n-3 PUFA content. A set of complementary approaches was used to study the impact of such a supplementation on the gut microbiota and host lipid/fatty acid (FA) metabolism. L. helveticus-supplementation was associated with a decrease in retinal saturated FAs (SFAs) and monounsaturated FAs (MUFAs) as well as an increase in retinal n-3 and omega-6 (n-6) PUFAs. Interestingly, supplementation with L. helveticus enriched the retina in C22:5n-3 (docosapentaenoic acid, DPA), C22:6n-3 (DHA), C18:2n-6 (linoleic acid, LA) and C20:3n-6 (dihomo gamma-linolenic acid, DGLA). Long-term consumption of L. helveticus also modulated gut microbiota composition and some changes in OTUs abundance correlated with the retinal FA content. This study provides a proof of concept that targeting the gut microbiota could be an effective strategy to modulate the retinal FA content, including that of protective n-3 PUFAs, thus opening paths for the design of novel preventive and/or therapeutical strategies for retinopathies.

Published
2024
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2. Lipoproteins LDL versus HDL as nanocarriers to target either cancer cells or macrophages

Author

Tarik Hadi, Christophe Ramseyer, Thomas Gautier, Pierre-Simon Bellaye, Tatiana Lopez, Antonin Schmitt, Sarah Foley, Semen Yesylevskyy, Thibault Minervini, Romain Douhard, Lucile Dondaine, Lil Proukhnitzky, Samir Messaoudi, Maeva Wendremaire, Mathieu Moreau, Fabrice Neiers, Bertrand Collin, Franck Denat, Laurent Lagrost, Carmen Garrido, and Frederic Lirussi

Subjects
Oncology, Therapeutics, Medicine
Abstract

In this work, we have explored natural unmodified low- and high-density lipoproteins (LDL and HDL, respectively) as selective delivery vectors in colorectal cancer therapy. We show in vitro in cultured cells and in vivo (NanoSPECT/CT) in the CT-26 mice colorectal cancer model that LDLs are mainly taken up by cancer cells, while HDLs are preferentially taken up by macrophages. We loaded LDLs with cisplatin and HDLs with the heat shock protein-70 inhibitor AC1LINNC, turning them into a pair of “Trojan horses” delivering drugs selectively to their target cells as demonstrated in vitro in human colorectal cancer cells and macrophages, and in vivo. Coupling of the drugs to lipoproteins and stability was assessed by mass spectometry and raman spectrometry analysis. Cisplatin vectorized in LDLs led to better tumor growth suppression with strongly reduced adverse effects such as renal or liver toxicity. AC1LINNC vectorized into HDLs induced a strong oxidative burst in macrophages and innate anticancer immune response. Cumulative antitumor effect was observed for both drug-loaded lipoproteins. Altogether, our data show that lipoproteins from patient blood can be used as natural nanocarriers allowing cell-specific targeting, paving the way toward more efficient, safer, and personalized use of chemotherapeutic and immunotherapeutic drugs in cancer.

Published
2020
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3. Human apolipoprotein C1 transgenesis reduces atherogenesis in hypercholesterolemic rabbits

Author

Erwana Harscoët, Naig Le Guern, Stéphanie Lemaire, Valérie Deckert, Bruno Da Silva, Geneviève Jolivet, Thomas Gautier, Lil Proukhnitzky, Marion Xolin, Amandine Bataille, Laurent Lagrost, Charlène Magnani, Virginie Aires, Louis-Marie Houdebine, David Masson, Guillaume Maquart, Danish Patoli, UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne (UB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Biologie du Développement [IBPS] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the University of Bourgogne Franche-Comté, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Fondation de France [Project Cardio 2013 R13057MM-RAF13002MMA to TG], ANR grant ATHEROLIP, the European Union program FEDER, and by a French Government grant managed by the French National Research Agency under the program ‘Investissements d’Avenir’ [reference ANR-11-LABX-0021 (Lipstic Labex)]., ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011), ANR-06-PHYS-0002,ATHEROLIP,Identification et caractérisation des propriétés proathérogènes des protéines plasmatiques de transfert des lipides (CETP et PLTP).(2006), European Project: FEDER, Jolivet, Geneviève, Laboratoires d'excellence - Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - - Lipstic2011 - ANR-11-LABX-0021 - LABX - VALID, Physiopathologie des maladies humaines (Physio) - Identification et caractérisation des propriétés proathérogènes des protéines plasmatiques de transfert des lipides (CETP et PLTP). - - ATHEROLIP2006 - ANR-06-PHYS-0002 - PHYSIO - VALID, Fonds Européens de Développement Régional - FEDER - INCOMING, Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire de Biologie du Développement [Paris] (LBD), and ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011)

Subjects
0301 basic medicine, medicine.medical_specialty, Very low-density lipoprotein, Apolipoprotein B, HDL, Transgene, Apolipoprotein C1, Endogeny, Rabbit, 030204 cardiovascular system & hematology, Transgenic, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], CETP, medicine, Animals, Humans, 2. Zero hunger, Apolipoprotein C-I, biology, Triglyceride, Cholesterol, Cholesterol, HDL, Gene Transfer Techniques, Atherosclerosis, Cholesterol Ester Transfer Proteins, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, carbohydrates (lipids), Transgenesis, 030104 developmental biology, Endocrinology, chemistry, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lipids (amino acids, peptides, and proteins), Rabbits, Cardiology and Cardiovascular Medicine
Abstract

International audience; Background and aims: Apolipoprotein (apo) C1 is a 6.6 kDa protein associated with HDL and VLDL. ApoC1 alters triglyceride clearance, and it also favors cholesterol accumulation in HDL, especially by inhibiting CETP in human plasma. Apart from studies in mice, which lack CETP, the impact of apoC1 on atherosclerosis in animal models expressing CETP, like in humans, is not known. This study aimed at determining the net effect of human apoC1 on atherosclerosis in rabbits, a species with naturally high CETP activity but with endogenous apoC1 without CETP inhibitory potential.Methods: Rabbits expressing a human apoC1 transgene (HuApoC1Tg) were generated and displayed significant amounts of human apoC1 in plasma.Results: After cholesterol feeding, atherosclerosis lesions were significantly less extensive (-22%, p < 0.05) and HDL displayed a reduced ability to serve as CETP substrates (-25%, p < 0.05) in HuApoC1Tg rabbits than in WT littermates. It was associated with rises in plasma HDL cholesterol level and PON-1 activity, and a decrease in the plasma level of the lipid oxidation markers 12(S)-HODE and 8(S)HETE. In chow-fed animals, the level of HDL-cholesterol was also significantly higher in HuApoC1Tg than in WT animals (0.83 ± 0.11 versus 0.73 ± 0.11 mmol/L, respectively, p < 0.05), and it was associated with significantly lower CETP activity (cholesteryl ester transfer rate, -10%, p < 0.05; specific CETP activity, -14%, p < 0.05).Conclusions: Constitutive expression of fully functional human apoC1 in transgenic rabbit attenuates atherosclerosis. It was found to relate, at least in part, to the inhibition of plasma CETP activity and to alterations in plasma HDL.

Published
2021
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4. Lipoproteins LDL versus HDL as nanocarriers to target either cancer cells or macrophages

Author

Lucile Dondaine, Carmen Garrido, Mathieu Moreau, Frédéric Lirussi, Romain Douhard, Samir Messaoudi, Christophe Ramseyer, Pierre-Simon Bellaye, Tatiana Lopez, Tarik Hadi, Sarah Foley, Laurent Lagrost, Lil Proukhnitzky, Thomas Gautier, Semen O. Yesylevskyy, Franck Denat, Fabrice Neiers, Antonin Schmitt, Maeva Wendremaire, Thibault Minervini, Bertrand Collin, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institute of Metal Physics of the National Academy of Sciences of Ukraine, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-CY Cergy Paris Université (CY), Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Messaoudi, Samir, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire Chrono-environnement (UMR 6249) (LCE), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Bourgogne (UB), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), and Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)

Subjects
0301 basic medicine, medicine.medical_treatment, cisplatin, lcsh:Medicine, heat shock protein inhibitor, Cancer immunotherapy, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Spectrum Analysis, Raman, Mice, Drug Delivery Systems, 0302 clinical medicine, Chemistry, selective cell targeting, General Medicine, 3. Good health, Lipoproteins, LDL, Oncology, 030220 oncology & carcinogenesis, Medicine, cancer therapy, lipids (amino acids, peptides, and proteins), Colorectal Neoplasms, Lipoproteins, HDL, Research Article, medicine.drug, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Lipoproteins, Therapeutics, Cell Line, 03 medical and health sciences, Immune system, In vivo, Cell Line, Tumor, medicine, vectorization, Animals, Humans, Cisplatin, Macrophages, lcsh:R, Cancer, medicine.disease, Colorectal cancer, In vitro, 030104 developmental biology, Cancer cell, Cancer research, Nanocarriers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

free open access article 31 p.; International audience; In this work, we have explored natural unmodified low- and high-density lipoproteins (LDL and HDL) as selective delivery vectors in colorectal cancer therapy. We show in vitro in cultured cells and in vivo (NanoSPECT/CT) in the CT-26 mice colorectal cancer model that LDLs are mainly taken up by cancer cells, while HDLs are preferentially taken up by macrophages. We loaded LDLs with cisplatin and HDLs with the heat shock protein-70 inhibitor AC1LINNC, turning them into a pair of “Trojan horses” delivering drugs selectively to their target cells as demonstrated in vitro in human colorectal cancer cells and macrophages, and in vivo. Coupling of the drugs to lipoproteins and stability was assessed by mass and raman spectrometry analysis. Cisplatin vectorized in LDLs led to better tumor growth suppression with strongly reduced adverse effects such as a renal or liver toxicity. AC1LINNC vectorized into HDLs induced a strong oxidative burst in macrophages and innate anti-cancer immune response. Cumulative anti-tumor effect was observed for both drug-loaded lipoproteins. Altogether, our data show that lipoproteins from patient’s blood can be used as natural nanocarriers allowing cell specific targeting, paving the way toward more efficient, safer and personalized use of chemo-and immunotherapeutic drugs in cancer

Published
2020
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