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Article: Intercellular Communication in the Brain through Tunneling Nanotubes.

Khattar, Khattar E / Safi, Janice / Rodriguez, Anne-Marie / Vignais, Marie-Luce

2022 Volume 14, Issue 5

Abstract: Intercellular communication is essential for tissue homeostasis and function. Understanding how cells interact with each other is paramount, as crosstalk between cells is often dysregulated in diseases and can contribute to their progression. Cells ... ...

Abstract	Intercellular communication is essential for tissue homeostasis and function. Understanding how cells interact with each other is paramount, as crosstalk between cells is often dysregulated in diseases and can contribute to their progression. Cells communicate with each other through several modalities, including paracrine secretion and specialized structures ensuring physical contact between them. Among these intercellular specialized structures, tunneling nanotubes (TNTs) are now recognized as a means of cell-to-cell communication through the exchange of cellular cargo, controlled by a variety of biological triggers, as described here. Intercellular communication is fundamental to brain function. It allows the dialogue between the many cells, including neurons, astrocytes, oligodendrocytes, glial cells, microglia, necessary for the proper development and function of the brain. We highlight here the role of TNTs in connecting these cells, for the physiological functioning of the brain and in pathologies such as stroke, neurodegenerative diseases, and gliomas. Understanding these processes could pave the way for future therapies.
Language	English
Publishing date	2022-02-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14051207
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Article ; Online: Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Jean Nakhle / Anne-Marie Rodriguez / Marie-Luce Vignais

International Journal of Molecular Sciences, Vol 21, Iss 4405, p

2020 Volume 4405

Abstract: Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which ... ...

Abstract	Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.
Keywords	mitochondria ; electron transport chain (ETC) ; tricarboxylic acid (TCA) cycle ; mitochondrial DNA (mtDNA) ; metabolism ; mitochondria exchange ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer.

Nakhle, Jean / Rodriguez, Anne-Marie / Vignais, Marie-Luce

International journal of molecular sciences

2020 Volume 21, Issue 12

Abstract	Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.
MeSH term(s)	Citric Acid Cycle ; Electron Transport Chain Complex Proteins/metabolism ; Humans ; Metabolic Diseases/metabolism ; Metabolic Networks and Pathways ; Metabolomics ; Mitochondria/metabolism ; Neoplasms/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	Electron Transport Chain Complex Proteins ; Reactive Oxygen Species
Language	English
Publishing date	2020-06-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21124405
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Article ; Online: Transfer of Cardiac Mitochondria Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in a Preclinical Model of Ischemic Heart Disease.

Vignais, Marie-Luce / Levoux, Jennyfer / Sicard, Pierre / Khattar, Khattar / Lozza, Catherine / Gervais, Marianne / Mezhoud, Safia / Nakhle, Jean / Relaix, Frederic / Agbulut, Onnik / Fauconnier, Jeremy / Rodriguez, Anne-Marie

Cells

2023 Volume 12, Issue 4

Abstract: Background: The use of mesenchymal stem cells (MSCs) appears to be a promising therapeutic approach for cardiac repair after myocardial infarction. However, clinical trials have revealed the need to improve their therapeutic efficacy. Recent evidence ... ...

Abstract	Background: The use of mesenchymal stem cells (MSCs) appears to be a promising therapeutic approach for cardiac repair after myocardial infarction. However, clinical trials have revealed the need to improve their therapeutic efficacy. Recent evidence demonstrated that mitochondria undergo spontaneous transfer from damaged cells to MSCs, resulting in the activation of the cytoprotective and pro-angiogenic functions of recipient MSCs. Based on these observations, we investigated whether the preconditioning of MSCs with mitochondria could optimize their therapeutic potential for ischemic heart disease. Methods: Human MSCs were exposed to mitochondria isolated from human fetal cardiomyocytes. After 24 h, the effects of mitochondria preconditioning on the MSCs' function were analyzed both in vitro and in vivo. Results: We found that cardiac mitochondria-preconditioning improved the proliferation and repair properties of MSCs in vitro. Mechanistically, cardiac mitochondria mediate their stimulatory effects through the production of reactive oxygen species, which trigger their own degradation in recipient MSCs. These effects were further confirmed in vivo, as the mitochondria preconditioning of MSCs potentiated their therapeutic efficacy on cardiac function following their engraftment into infarcted mouse hearts. Conclusions: The preconditioning of MSCs with the artificial transfer of cardiac mitochondria appears to be promising strategy to improve the efficacy of MSC-based cell therapy in ischemic heart disease.
MeSH term(s)	Mice ; Animals ; Humans ; Myocardial Ischemia/metabolism ; Myocardial Infarction/metabolism ; Myocytes, Cardiac/metabolism ; Mitochondria, Heart/metabolism ; Mesenchymal Stem Cells/metabolism
Language	English
Publishing date	2023-02-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12040582
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Article ; Online: Transfer of mesenchymal stem cell mitochondria to CD4+ T cells contributes to repress Th1 differentiation by downregulating T-bet expression

Waseem Akhter / Jean Nakhle / Loïc Vaillant / Geneviève Garcin / Cécile Le Saout / Matthieu Simon / Carole Crozet / Farida Djouad / Christian Jorgensen / Marie-Luce Vignais / Javier Hernandez

Stem Cell Research & Therapy, Vol 14, Iss 1, Pp 1-

2023 Volume 16

Abstract: Abstract Background Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show ... ...

Abstract	Abstract Background Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show therapeutic potential for the treatment of autoimmune diseases, organ rejection and graft versus host disease. MSCs have the remarkable ability to export their own mitochondria to neighboring cells in response to injury and inflammation. However, whether mitochondrial transfer occurs and has any role in the repression of CD4+ Th1 responses is unknown. Methods and results In this report we have utilized CD4+ T cells from HNT TCR transgenic mice that develop Th1-like responses upon antigenic stimulation in vitro and in vivo. Allogeneic bone marrow-derived MSCs reduced the diabetogenic potential of HNT CD4+ T cells in vivo in a transgenic mouse model of disease. In co-culture experiments, we have shown that MSCs were able to reduce HNT CD4+ T cell expansion, expression of key effector markers and production of the effector cytokine IFNγ after activation. This was associated with the ability of CD4+ T cells to acquire mitochondria from MSCs as evidenced by FACS and confocal microscopy. Remarkably, transfer of isolated MSC mitochondria to CD4+ T cells resulted in decreased T cell proliferation and IFNγ production. These effects were additive with those of prostaglandin E2 secreted by MSCs. Finally, we demonstrated that both co-culture with MSCs and transfer of isolated MSC mitochondria prevent the upregulation of T-bet, the master Th1 transcription factor, on activated CD4+ T cells. Conclusion The present study demonstrates that transfer of MSC mitochondria to activated CD4+ T cells results in the suppression of Th1 responses in part by downregulating T-bet expression. Furthermore, our studies suggest that MSC mitochondrial transfer might represent a general mechanism of MSC-dependent immunosuppression.
Keywords	Mesenchymal stem/stromal cells ; CD4+ T cells ; Mitochondrial transfer ; Immunotherapy ; Autoimmunity ; Medicine (General) ; R5-920 ; Biochemistry ; QD415-436
Subject code	570
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Methods for simultaneous and quantitative isolation of mitochondrial DNA, nuclear DNA and RNA from mammalian cells

Jean Nakhle / Tülin Özkan / Kateřina Lněničková / Philippe Briolotti / Marie-Luce Vignais

BioTechniques, Vol 69, Iss 6, Pp 436-

2020 Volume 442

Abstract: The aim of this study was to assess two protocols for their capacities to simultaneously isolate RNA, mtDNA and ncDNA from mammalian cells. We compared the Invitrogen TRIzol-based method and Qiagen DNeasy columns, using the HepG2 cell line and human ... ...

Abstract	The aim of this study was to assess two protocols for their capacities to simultaneously isolate RNA, mtDNA and ncDNA from mammalian cells. We compared the Invitrogen TRIzol-based method and Qiagen DNeasy columns, using the HepG2 cell line and human primary glioblastoma stem cells. Both methods allowed the isolation of all three types of nucleic acids and provided similar yields in mtDNA. However, the yield in ncDNA was more than tenfold higher on columns, as observed for both cell types. Conversely, the TRIzol method proved more reproducible and was the method of choice for isolating RNA from glioblastoma cells, as demonstrated for the housekeeping genes RPLP0 and RPS9.
Keywords	mammalian cells ; mitochondria ; mitochondrial DNA (mtDNA) ; nuclear DNA (ncDNA) ; RNA ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Future Science Ltd
Document type	Article ; Online
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Article ; Online: Transfer of mesenchymal stem cell mitochondria to CD4

Akhter, Waseem / Nakhle, Jean / Vaillant, Loïc / Garcin, Geneviève / Le Saout, Cécile / Simon, Matthieu / Crozet, Carole / Djouad, Farida / Jorgensen, Christian / Vignais, Marie-Luce / Hernandez, Javier

Stem cell research & therapy

2023 Volume 14, Issue 1, Page(s) 12

Abstract: Background: Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show therapeutic ... ...

Abstract	Background: Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show therapeutic potential for the treatment of autoimmune diseases, organ rejection and graft versus host disease. MSCs have the remarkable ability to export their own mitochondria to neighboring cells in response to injury and inflammation. However, whether mitochondrial transfer occurs and has any role in the repression of CD4 Methods and results: In this report we have utilized CD4 Conclusion: The present study demonstrates that transfer of MSC mitochondria to activated CD4
MeSH term(s)	Animals ; Mice ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/physiology ; Cell Differentiation ; Cells, Cultured ; Cytokines/metabolism ; Mesenchymal Stem Cells/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondria/physiology ; T-Lymphocytes, Regulatory ; Th17 Cells ; Th1 Cells/metabolism
Chemical Substances	Cytokines ; T-box transcription factor TBX21
Language	English
Publishing date	2023-01-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-022-03219-x
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Article ; Online: Methods for simultaneous and quantitative isolation of mitochondrial DNA, nuclear DNA and RNA from mammalian cells.

Nakhle, Jean / Özkan, Tülin / Lněničková, Kateřina / Briolotti, Philippe / Vignais, Marie-Luce

BioTechniques

2020 Volume 69, Issue 6, Page(s) 436–442

Abstract	The aim of this study was to assess two protocols for their capacities to simultaneously isolate RNA, mtDNA and ncDNA from mammalian cells. We compared the Invitrogen TRIzol-based method and Qiagen DNeasy columns, using the HepG2 cell line and human primary glioblastoma stem cells. Both methods allowed the isolation of all three types of nucleic acids and provided similar yields in mtDNA. However, the yield in ncDNA was more than tenfold higher on columns, as observed for both cell types. Conversely, the TRIzol method proved more reproducible and was the method of choice for isolating RNA from glioblastoma cells, as demonstrated for the housekeeping genes
MeSH term(s)	Animals ; Biochemistry/methods ; Cell Nucleus/metabolism ; DNA, Mitochondrial/isolation & purification ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Hep G2 Cells ; Humans ; Mammals/metabolism ; Neoplastic Stem Cells/metabolism ; RNA/isolation & purification ; RNA, Messenger/isolation & purification ; Reagent Kits, Diagnostic
Chemical Substances	DNA, Mitochondrial ; RNA, Messenger ; Reagent Kits, Diagnostic ; RNA (63231-63-0)
Language	English
Publishing date	2020-10-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	48453-2
ISSN	1940-9818 ; 0736-6205
ISSN (online)	1940-9818
ISSN	0736-6205
DOI	10.2144/btn-2020-0114
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Article ; Online: Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury.

Rodriguez, Anne-Marie / Nakhle, Jean / Griessinger, Emmanuel / Vignais, Marie-Luce

Cell cycle (Georgetown, Tex.)

2018 Volume 17, Issue 6, Page(s) 712–721

Abstract: Mitochondria are crucial organelles that not only regulate the energy metabolism, but also the survival and fate of eukaryotic cells. Mitochondria were recently discovered to be able to translocate from one cell to the other. This phenomenon was observed ...

Abstract	Mitochondria are crucial organelles that not only regulate the energy metabolism, but also the survival and fate of eukaryotic cells. Mitochondria were recently discovered to be able to translocate from one cell to the other. This phenomenon was observed in vitro and in vivo, both in physiological and pathophysiological conditions including tissue injury and cancer. Mitochondria trafficking was found to exert prominent biological functions. In particular, several studies pointed out that this process governs some of the therapeutic effects of mesenchymal stem cells (MSCs). In this review, we give an overview of the current knowledge on MSC-dependent intercellular mitochondria trafficking and further discuss the recent findings on the intercellular mitochondria transfer between differentiated and mesenchymal stem cells, their biological significance and the mechanisms underlying this process.
MeSH term(s)	Animals ; Cell Differentiation ; DNA, Mitochondrial/metabolism ; Humans ; Inflammation/prevention & control ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Mitochondria/metabolism ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/therapy
Chemical Substances	DNA, Mitochondrial
Language	English
Publishing date	2018-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2018.1445906
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Article ; Online: The role of metabolism and tunneling nanotube-mediated intercellular mitochondria exchange in cancer drug resistance.

Hekmatshoar, Yalda / Nakhle, Jean / Galloni, Mireille / Vignais, Marie-Luce

The Biochemical journal

2018 Volume 475, Issue 14, Page(s) 2305–2328

Abstract: Intercellular communications play a major role in tissue homeostasis. In pathologies such as cancer, cellular interactions within the tumor microenvironment (TME) contribute to tumor progression and resistance to therapy. Tunneling nanotubes (TNTs) are ... ...

Abstract	Intercellular communications play a major role in tissue homeostasis. In pathologies such as cancer, cellular interactions within the tumor microenvironment (TME) contribute to tumor progression and resistance to therapy. Tunneling nanotubes (TNTs) are newly discovered long-range intercellular connections that allow the exchange between cells of various cargos, ranging from ions to whole organelles such as mitochondria. TNT-transferred mitochondria were shown to change the metabolism and functional properties of recipient cells as reported for both normal and cancer cells. Metabolic plasticity is now considered a hallmark of cancer as it notably plays a pivotal role in drug resistance. The acquisition of cancer drug resistance was also associated to TNT-mediated mitochondria transfer, a finding that relates to the role of mitochondria as a hub for many metabolic pathways. In this review, we first give a brief overview of the various mechanisms of drug resistance and of the cellular communication means at play in the TME, with a special focus on the recently discovered TNTs. We further describe recent studies highlighting the role of the TNT-transferred mitochondria in acquired cancer cell drug resistance. We also present how changes in metabolic pathways, including glycolysis, pentose phosphate and lipid metabolism, are linked to cancer cell resistance to therapy. Finally, we provide examples of novel therapeutic strategies targeting mitochondria and cell metabolism as a way to circumvent cancer cell drug resistance.
MeSH term(s)	Animals ; Drug Resistance, Neoplasm ; Humans ; Mitochondria/metabolism ; Mitochondria/pathology ; Nanotubes ; Neoplasms/metabolism ; Neoplasms/pathology ; Tumor Microenvironment
Language	English
Publishing date	2018-07-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20170712
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