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Article: Tauroursodeoxycholic acid: more than just a neuroprotective bile conjugate.

Romero-Ramírez, Lorenzo / Nieto-Sampedro, Manuel / Yanguas-Casás, Natalia

2017 Volume 12, Issue 1, Page(s) 62–63

Language	English
Publishing date	2017-02-08
Publishing country	India
Document type	Journal Article
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.198979
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Aldynoglia cells and modulation of RhoGTPase activity as useful tools for spinal cord injury repair.

Doncel-Pérez, Ernesto / Nieto-Sampedro, Manuel

Neural regeneration research

2016 Volume 11, Issue 7, Page(s) 1043–1045

Abstract: A combined approach in spinal cord injury (SCI) therapy is the modulation of the cellular and molecular processes involved in glial scarring. Aldaynoglial cells are neural cell precursors with a high capacity to differentiate into neurons, promote axonal ...

Abstract	A combined approach in spinal cord injury (SCI) therapy is the modulation of the cellular and molecular processes involved in glial scarring. Aldaynoglial cells are neural cell precursors with a high capacity to differentiate into neurons, promote axonal growth, wrapping and myelination of resident neurons. These important characteristics of aldaynoglia can be combined with specific inhibition of the RhoGTPase activity in astroglia and microglia that cause reduction of glial proliferation, retraction of glial cell processes and myelin production by oligodendrocytes. Previously we used experimental central nervous system (CNS) injury models, like spinal cord contusion and striatal lacunar infarction and observed that administration of RhoGTPase glycolipid inhibitor or aldaynoglial cells, respectively, produced a significant gain of functional recovery in treated animals. The combined therapy with neuro-regenerative properties strategy is highly desirable to treat SCI for functional potentiation of neurons and oligodendrocytes, resulting in better locomotor recovery. Here we suggest that treatment of spinal lesions with aldaynoglia from neurospheres plus local administration of a RhoGTPase inhibitor could have an additive effect and promote recovery from SCI.
Language	English
Publishing date	2016-08-31
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.187020
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Article ; Online: Integrated Stress Response as a Therapeutic Target for CNS Injuries.

Romero-Ramírez, Lorenzo / Nieto-Sampedro, Manuel / Barreda-Manso, M Asunción

BioMed research international

2017 Volume 2017, Page(s) 6953156

Abstract: Central nervous system (CNS) injuries, caused by cerebrovascular pathologies or mechanical contusions (e.g., traumatic brain injury, TBI) comprise a diverse group of disorders that share the activation of the integrated stress response (ISR). This ... ...

Abstract	Central nervous system (CNS) injuries, caused by cerebrovascular pathologies or mechanical contusions (e.g., traumatic brain injury, TBI) comprise a diverse group of disorders that share the activation of the integrated stress response (ISR). This pathway is an innate protective mechanism, with encouraging potential as therapeutic target for CNS injury repair. In this review, we will focus on the progress in understanding the role of the ISR and we will discuss the effects of various small molecules that target the ISR on different animal models of CNS injury.
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2698540-8
ISSN	2314-6141 ; 2314-6133
ISSN (online)	2314-6141
ISSN	2314-6133
DOI	10.1155/2017/6953156
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Article: All roads go to Salubrinal: endoplasmic reticulum stress, neuroprotection and glial scar formation.

Romero-Ramírez, Lorenzo / Nieto-Sampedro, Manuel / Barreda-Manso, M Asunción

Neural regeneration research

2016 Volume 10, Issue 12, Page(s) 1926–1927

Language	English
Publishing date	2016-01-14
Publishing country	India
Document type	Journal Article
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.169619
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Article ; Online: Neurostatin and other O-acetylated gangliosides show anti-neuroinflammatory activity involving the NFκB pathway.

Yanguas-Casás, Natalia / Ojalvo-Sanz, Ana Cristina / Martínez-Vázquez, Aroa / Goneau, Marie-France / Gilbert, Michel / Nieto-Sampedro, Manuel / Romero-Ramírez, Lorenzo

Toxicology and applied pharmacology

2019 Volume 377, Page(s) 114627

Abstract: In many neuropathologies activated microglia and macrophages cause neurotoxicity and prolong the inflammatory response. We have previously characterized the glycosphingolipid Neurostatin (Nst), which potentially reduces these detrimental mechanisms. Nst, ...

Abstract	In many neuropathologies activated microglia and macrophages cause neurotoxicity and prolong the inflammatory response. We have previously characterized the glycosphingolipid Neurostatin (Nst), which potentially reduces these detrimental mechanisms. Nst, isolated from mammalian brain, is the GD1b ganglioside with O-acetylation of the outer sialic acid residue. Using the enzyme sialate-O-acetyltransferase (SOAT), we obtained several O-acetylated gangliosides and O-propionylated GD1b (PrGD1b). In the present study we investigated the anti-inflammatory effects of these compounds. Nst and other O-acetylated gangliosides reduced nitrite production in microglial cells which were activated with lipopolysaccharide (LPS), but did not affect nitrite production after their stimulation with interferon gamma (IFNγ). Structure-activity relationship analysis showed that Nst was the most active ganglioside as inhibitor of nitrite production. Its ceramide moiety is essential for this, and both, the O-acetylation and the monosaccharide chain are important for the anti-inflammatory activity of the gangliosides. We also found that Nst reduced iNOS, IL-6 and IL-12 transcription in LPS-induced microglia, likely by inhibiting nuclear localization of NFκB. In co-cultures, Nst reduced neuronal cell death caused by LPS-activated microglia. In vivo, Nst diminished microglia activation in a mouse model of acute neuroinflammation. We propose that Nst and other O-acetylated gangliosides are neuroprotective regulators of microglia activity under both physiological and pathological conditions.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Cell Line ; Encephalitis/prevention & control ; Gangliosides/pharmacology ; Glycosphingolipids/pharmacology ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/drug effects ; NF-kappa B/drug effects ; Neuroprotective Agents/pharmacology ; Organic Anion Transporters/metabolism ; Rats ; Rats, Wistar ; Signal Transduction/drug effects
Chemical Substances	Anti-Inflammatory Agents ; Gangliosides ; Glycosphingolipids ; Lipopolysaccharides ; NF-kappa B ; Neuroprotective Agents ; Organic Anion Transporters ; Slc10a6 protein, rat ; neurostatin ; ganglioside, GD1b (19553-76-5)
Language	English
Publishing date	2019-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2019.114627
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Article ; Online: Neuroprotection and Blood-Brain Barrier Restoration by Salubrinal After a Cortical Stab Injury.

Barreda-Manso, M Asunción / Yanguas-Casás, Natalia / Nieto-Sampedro, Manuel / Romero-Ramírez, Lorenzo

Journal of cellular physiology

2017 Volume 232, Issue 6, Page(s) 1501–1510

Abstract: Following a central nervous system (CNS) injury, restoration of the blood-brain barrier (BBB) integrity is essential for recovering homeostasis. When this process is delayed or impeded, blood substances and cells enter the CNS parenchyma, initiating an ... ...

Abstract	Following a central nervous system (CNS) injury, restoration of the blood-brain barrier (BBB) integrity is essential for recovering homeostasis. When this process is delayed or impeded, blood substances and cells enter the CNS parenchyma, initiating an additional inflammatory process that extends the initial injury and causes so-called secondary neuronal loss. Astrocytes and profibrotic mesenchymal cells react to the injury and migrate to the lesion site, creating a new glia limitans that restores the BBB. This process is beneficial for the resolution of the inflammation, neuronal survival, and the initiation of the healing process. Salubrinal is a small molecule with neuroprotective properties in different animal models of stroke and trauma to the CNS. Here, we show that salubrinal increased neuronal survival in the neighbourhood of a cerebral cortex stab injury. Moreover, salubrinal reduced cortical blood leakage into the parenchyma of injured animals compared with injured controls. Adjacent to the site of injury, salubrinal induced immunoreactivity for platelet-derived growth factor subunit B (PDGF-B), a specific mitogenic factor for mesenchymal cells. This effect might be responsible for the increased immunoreactivity for fibronectin and the decreased activation of microglia and macrophages in injured mice treated with salubrinal, compared with injured controls. The immunoreactivity for PDGF-B colocalized with neuronal nuclei (NeuN), suggesting that cortical neurons in the proximity of the injury were the main source of PDGF-B. Our results suggest that after an injury, neurons play an important role in both, the healing process and the restoration of the BBB integrity. J. Cell. Physiol. 232: 1501-1510, 2017. © 2016 Wiley Periodicals, Inc.
MeSH term(s)	Animals ; Astrocytes/drug effects ; Astrocytes/metabolism ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/pathology ; Brain Injuries/drug therapy ; Brain Injuries/pathology ; Calcium-Binding Proteins/metabolism ; Cell Survival/drug effects ; Cerebral Cortex/injuries ; Cerebral Cortex/pathology ; Cinnamates/pharmacology ; Cinnamates/therapeutic use ; Disease Models, Animal ; Evans Blue/metabolism ; Fibronectins/metabolism ; Male ; Mice, Inbred C57BL ; Microfilament Proteins/metabolism ; Models, Biological ; Neurons/drug effects ; Neurons/pathology ; Neuroprotection/drug effects ; Platelet-Derived Growth Factor/metabolism ; Signal Transduction/drug effects ; Thiourea/analogs & derivatives ; Thiourea/pharmacology ; Thiourea/therapeutic use ; Transforming Growth Factor beta/metabolism ; Wounds, Stab/drug therapy ; Wounds, Stab/pathology
Chemical Substances	Aif1 protein, mouse ; Calcium-Binding Proteins ; Cinnamates ; Fibronectins ; Microfilament Proteins ; Platelet-Derived Growth Factor ; Transforming Growth Factor beta ; salubrinal ; Evans Blue (45PG892GO1) ; Thiourea (GYV9AM2QAG)
Language	English
Publishing date	2017-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.25655
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Article ; Online: TUDCA: An Agonist of the Bile Acid Receptor GPBAR1/TGR5 With Anti-Inflammatory Effects in Microglial Cells.

Yanguas-Casás, Natalia / Barreda-Manso, M Asunción / Nieto-Sampedro, Manuel / Romero-Ramírez, Lorenzo

Journal of cellular physiology

2017 Volume 232, Issue 8, Page(s) 2231–2245

Abstract: Bile acids are steroid acids found in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of stroke and neurological diseases. We have previously shown that TUDCA has anti- ... ...

Abstract	Bile acids are steroid acids found in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of stroke and neurological diseases. We have previously shown that TUDCA has anti-inflammatory effects on glial cell cultures and in a mouse model of acute neuroinflammation. We show now that microglial cells (central nervous system resident macrophages) express the G protein-coupled bile acid receptor 1/Takeda G protein-coupled receptor 5 (GPBAR1/TGR5) in vivo and in vitro. TUDCA binding to GPBAR1/TGR5 caused an increase in intracellular cAMP levels in microglia that induced anti-inflammatory markers, while reducing pro-inflammatory ones. This anti-inflammatory effect of TUDCA was inhibited by small interference RNA for GPBAR1/TGR5 receptor, as well as by treatment with a protein kinase A (PKA) inhibitor. In the mouse model of acute neuroinflammation, treating the animals with TUDCA was clearly anti-inflammatory. TUDCA biased the microglial phenotype in vivo and in vitro toward the anti-inflammatory. The bile acid receptor GPBAR1/TGR5 could be a new therapeutic target for pathologies coursing with neuroinflammation and microglia activation, such as traumatic brain injuries, stroke, or neurodegenerative diseases. TUDCA and other GPBAR1/TGR5 agonists need to be further investigated, to determine their potential in attenuating the neuropathologies associated with microglia activation. J. Cell. Physiol. 232: 2231-2245, 2017. © 2016 Wiley Periodicals, Inc.
MeSH term(s)	Animals ; Animals, Newborn ; Anti-Inflammatory Agents/pharmacology ; Cells, Cultured ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Disease Models, Animal ; Encephalitis/genetics ; Encephalitis/metabolism ; Encephalitis/pathology ; Encephalitis/prevention & control ; Hippocampus/drug effects ; Hippocampus/metabolism ; Hippocampus/pathology ; Inflammation Mediators/metabolism ; Mice, Inbred C57BL ; Microglia/drug effects ; Microglia/metabolism ; Microglia/pathology ; Neuroprotective Agents/pharmacology ; Prosencephalon/drug effects ; Prosencephalon/metabolism ; Prosencephalon/pathology ; Protein Kinase Inhibitors/pharmacology ; RNA Interference ; Rats, Wistar ; Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/drug effects ; Taurochenodeoxycholic Acid/pharmacology ; Time Factors ; Transfection
Chemical Substances	Anti-Inflammatory Agents ; Gpbar1 protein, mouse ; Gpbar1 protein, rat ; Inflammation Mediators ; Neuroprotective Agents ; Protein Kinase Inhibitors ; Receptors, G-Protein-Coupled ; Taurochenodeoxycholic Acid (516-35-8) ; tauroursodeoxycholic acid (60EUX8MN5X) ; Cyclic AMP (E0399OZS9N) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
Language	English
Publishing date	2017-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.25742
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Article ; Online: Influence of chitosan concentration on cell viability and proliferation in vitro by changing film topography.

Martín-López, Eduardo / Nieto-Díaz, Manuel / Nieto-Sampedro, Manuel

Journal of applied biomaterials & functional materials

2013 Volume 11, Issue 3, Page(s) e151–8

Abstract: Purpose: Chitosan is a natural polysaccharide which can form gels and scaffolds that support its use as a biomaterial in various tissue engineering applications. A useful feature of chitosan polymer is that you can manipulate its properties easily. Thus, ...

Abstract	Purpose: Chitosan is a natural polysaccharide which can form gels and scaffolds that support its use as a biomaterial in various tissue engineering applications. A useful feature of chitosan polymer is that you can manipulate its properties easily. Thus, in this work we studied the effect of varying chitosan concentration in the topography and the biological properties of the chitosan films, as well as the effects in the structure of 3D gels in order to be used as nerve bridges. Methods: Analysis of film topographies were addressed by swelling test and atomic force microscopy (AFM). In vitro biological properties were assessed through MTT viability assays on cultures of blood-brain barrier forming endothelial (bEnd5), glioma (C6) and postmitotic neuron (NGF-differentiated PC12) cell lines. The structure of tridimensional gels was studied by environmental scanning electron microscopy.  Results: Topography of 1% chitosan films showed a AFM profile with higher nano-roughness profile than that observed in 2% films, which was smoother. Moreover, swelling rate was not affected. Topography changes affected cell viability as shown by the MTT assays. Our results showed that 2% chitosan films promoted higher proliferation and viability of C6 and PC12 respectively than 1% films. Conversely, neither 1% nor 2% films promoted viability of bEnd5 cells. In order to establish the feasibility of both type of chitosan solutions as nerve bridges, we constructed 3D gels by alkaline precipitation. Resulting gels showed that only 2% gels were rigid enough to be effectively used as nerve bridges. Conclusions: These results establish that changes in chitosan concentration affects the polymer surface topography, which has a direct effect in the growing cell behavior. Additionally, higher concentration of chitosan gels are required to be used in neural tissue engineering.
MeSH term(s)	Animals ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chitosan/chemistry ; Chitosan/pharmacology ; Microscopy, Atomic Force ; PC12 Cells ; Rats ; Surface Properties ; Tissue Engineering
Chemical Substances	Chitosan (9012-76-4)
Language	English
Publishing date	2013-12-16
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2673624-X
ISSN	2280-8000 ; 1722-6899
ISSN (online)	2280-8000
ISSN	1722-6899
DOI	10.5301/JABFM.2012.10449
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Article ; Online: Integrated Stress Response as a Therapeutic Target for CNS Injuries

Lorenzo Romero-Ramírez / Manuel Nieto-Sampedro / M. Asunción Barreda-Manso

BioMed Research International, Vol

2017 Volume 2017

Abstract	Central nervous system (CNS) injuries, caused by cerebrovascular pathologies or mechanical contusions (e.g., traumatic brain injury, TBI) comprise a diverse group of disorders that share the activation of the integrated stress response (ISR). This pathway is an innate protective mechanism, with encouraging potential as therapeutic target for CNS injury repair. In this review, we will focus on the progress in understanding the role of the ISR and we will discuss the effects of various small molecules that target the ISR on different animal models of CNS injury.
Keywords	Medicine ; R
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differential adhesiveness and neurite-promoting activity for neural cells of chitosan, gelatin, and poly-L-lysine films.

Martín-López, Eduardo / Nieto-Díaz, Manuel / Nieto-Sampedro, Manuel

Journal of biomaterials applications

2012 Volume 26, Issue 7, Page(s) 791–809

Abstract: Chitosan (Ch) and some of its derivatives have been proposed as good biomaterials for tissue engineering, to construct scaffolds promoting tissue regeneration. In this work we made composite films from Ch and mixtures of Ch with gelatin (G) and poly-l- ... ...

Abstract	Chitosan (Ch) and some of its derivatives have been proposed as good biomaterials for tissue engineering, to construct scaffolds promoting tissue regeneration. In this work we made composite films from Ch and mixtures of Ch with gelatin (G) and poly-l-lysine (PLL), and evaluated the growth on these films of PC12 and C6 lines as well as neurons and glial cells derived from cerebral tissue and dorsal root ganglia (DRG). C6 glioma cells proliferated on Ch, G, and Ch + G films, although metabolic activity was decreased by the presence of the G in the mixtures. NGF-differentiated PC12 cells, adhered preferentially on Ch and films containing PLL. Unlike NGF-treated PC12 cells, cortical and hippocampal neurons showed good adhesion to Ch and Ch + G films, where they extended neurites. Astrocytes adhered on Ch, Ch + G, and Ch + PLL mixtures, although viability decreased during the culture time. Olfactory ensheathing cells (OEC) adhered and proliferated to confluency on the wells covered with Ch + G films. Neurites from DRGs exhibited high extension on these films. These results demonstrate that Ch + G films have excellent adhesive properties for both neurons and regeneration-promoting glia (OEC). These films also promoted neurite extension from DRG, making them good candidates for tissue engineering of nerve repair.
MeSH term(s)	Animals ; Cell Adhesion ; Cell Line, Tumor ; Cell Proliferation ; Cells, Cultured ; Chitosan/chemistry ; Ganglia, Spinal/cytology ; Gelatin/chemistry ; Neurites/metabolism ; Neuroglia/cytology ; Neuroglia/metabolism ; Neurons/cytology ; Neurons/metabolism ; PC12 Cells ; Polylysine/chemistry ; Rats ; Rats, Wistar ; Tissue Scaffolds/chemistry
Chemical Substances	gelatin film ; Polylysine (25104-18-1) ; Gelatin (9000-70-8) ; Chitosan (9012-76-4)
Language	English
Publishing date	2012-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639283-0
ISSN	1530-8022 ; 0885-3282
ISSN (online)	1530-8022
ISSN	0885-3282
DOI	10.1177/0885328210379928
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