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Article: Editorial: New insights into the role of neuroinflammation and glial cells in the development of neurological disorders.

Pérez-González, Marta / Solas, Maite / Wu, Yixing / Mela, Virginia

2023 Volume 17, Page(s) 1170013

Language	English
Publishing date	2023-03-14
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2023.1170013
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Article: Microglia isolation from aging mice for cell culture: A beginner's guide.

Vijaya, Akshay Kumar / Iešmantaitė, Monika / Mela, Virginia / Baltriukienė, Daiva / Burokas, Aurelijus

Frontiers in cellular neuroscience

2023 Volume 17, Page(s) 1082180

Abstract: Microglia, the innate immune cell of the central nervous system, play significant roles in brain development, maintenance, homeostasis, and neuroinflammation. Although numerous methods have been developed to isolate microglia from embryonic or postnatal ... ...

Abstract	Microglia, the innate immune cell of the central nervous system, play significant roles in brain development, maintenance, homeostasis, and neuroinflammation. Although numerous methods have been developed to isolate microglia from embryonic or postnatal mouse brains, still major difficulties exist in isolating microglia from adult mice, often resulting in low yield and risk of cellular activation. Therefore, there is a need for a more efficient method to isolate pure and high-yield microglia from adult mice to study various neurodegenerative diseases. The aim of this study was to develop a fully functional protocol for the isolation of microglia by comparing different protocols. We investigated the efficacy of three protocols in terms of cell yield, purity, cellular activation, cellular aging, and migration properties and proposed the modified protocol (PROTOCOL 1), which provides an optimal yield of functional microglial cells with a minimum of material and equipment and allows young researchers with little experience to isolate microglia and helps them to delve deeper into the world of neuroscience.
Language	English
Publishing date	2023-01-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2023.1082180
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Article ; Online: Acute Stress, Induced by IFNγ + Aβ, and Chronic Stress, Induced by Age, Affect Microglia in a Sex-Specific Manner.

Mela, Virginia / Gaban, Aline Sayd / Shatz, Paul Marie / Guillot-Sestier, Marie-Victoire / Lynch, Marina A

Molecular neurobiology

2023 Volume 60, Issue 6, Page(s) 3044–3053

Abstract: Microglial phenotype changes in the aged brain, and also in neurodegenerative diseases, and it is generally accepted that these changes at least contribute to the inflammation that can have detrimental effects on brain health. Accumulating data have ... ...

Abstract	Microglial phenotype changes in the aged brain, and also in neurodegenerative diseases, and it is generally accepted that these changes at least contribute to the inflammation that can have detrimental effects on brain health. Accumulating data have determined that there are multiple microglial activation states with consistent findings indicating that with stressors including age, a switch towards an inflammatory phenotype occurs. Among the changes that accompany this is a change in metabolism, whereby glycolysis is increased in microglia. Here, we asked whether sex impacted on the response of microglia to two stressors, interferon-γ + amyloid-β (IFNγ + Aβ) and age. The data show that IFNγ + Aβ triggered cells from female mice to adopt a glycolytic phenotype. Metabolism was also altered with age; microglia from aged male mice responded by increasing oxidative phosphorylation, and microglial motility was preserved, contrasting with microglia from female mice where motility was compromised. We conclude that sex is a significant variable in the responses of microglia to stressors.
MeSH term(s)	Animals ; Female ; Male ; Mice ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Inflammation/metabolism ; Interferon-gamma/metabolism ; Microglia/metabolism ; Aging
Chemical Substances	Amyloid beta-Peptides ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2023-02-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-023-03235-9
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Zs.A 2411: Show issues

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Jg. 1995 - 2021: Lesesall (2.OG)
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Article ; Online: The Postnatal Leptin Surge Supports Immune Cell Function in Rats.

Hunsche, Caroline / Hernandez, Oskarina / Mela, Virginia / Viveros, M Paz / De la Fuente, Mónica

Immunological investigations

2021 Volume 51, Issue 5, Page(s) 1347–1363

Abstract: Background: Leptin plays an important role in the regulation of the immune response. There is a physiological surge of leptin in rodents during the neonatal period, which has mainly been studied in the context of brain development. However, little is ... ...

Abstract	Background: Leptin plays an important role in the regulation of the immune response. There is a physiological surge of leptin in rodents during the neonatal period, which has mainly been studied in the context of brain development. However, little is known about the effects of this neonatal leptin surge on immunity. Therefore, we investigated whether blocking this leptin surge could affect several immune functions. Methods: Male and female rats were injected subcutaneously with 5 mg/Kg/day of rat pegylated super leptin antagonist during the neonatal period (PND5-9). On the peripubertal period, relevant functions as well as cytokine release by spleen leukocytes were studied in these animals. Results: The results showed that the animals significantly display an impaired anti-tumor NK activity and chemotactic and proliferation capacity of lymphocytes in response to mitogens. In addition, several cytokine concentrations, released under mitogen-stimulated conditions, were also altered. Conclusion: In conclusion, the neonatal leptin surge seems to be involved in the establishment of an adequate immune response and cytokine profile, which are crucial for the maintenance of a healthy life.
MeSH term(s)	Animals ; Animals, Newborn/growth & development ; Animals, Newborn/immunology ; Cytokines/analysis ; Cytokines/immunology ; Female ; Growth and Development/immunology ; Immunity/immunology ; Immunity/physiology ; Intercellular Signaling Peptides and Proteins/immunology ; Leptin/immunology ; Male ; Rats/immunology
Chemical Substances	Cytokines ; Intercellular Signaling Peptides and Proteins ; Leptin
Language	English
Publishing date	2021-06-14
Publishing country	England
Document type	Journal Article
ZDB-ID	632565-8
ISSN	1532-4311 ; 0882-0139
ISSN (online)	1532-4311
ISSN	0882-0139
DOI	10.1080/08820139.2021.1940199
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Zs.A 988: Show issues

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Article ; Online: The Modulatory Effects of DMF on Microglia in Aged Mice Are Sex-Specific.

Mela, Virginia / Sayd Gaban, Aline / O'Neill, Eoin / Bechet, Sibylle / Walsh, Aífe / Lynch, Marina A

Cells

2022 Volume 11, Issue 4

Abstract: There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several ... ...

Abstract	There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several neurodegenerative diseases and is considered to be a key factor in driving the inflammation that characterizes these conditions. Among the changes that have been described is a switch in microglial metabolism towards glycolysis which is associated with production of inflammatory mediators and reduced function. Marked sex-related differences in microglial number, phenotype and function have been described in late embryonic and early postnatal life in rodents and some reports suggest that sexual dimorphism extends into adulthood and age and, in models of Alzheimer's disease, the changes are more profound in microglia from female, compared with male, mice. Dimethyl fumarate (DMF) is a fumaric acid ester used in the treatment of psoriasis and relapsing remitting multiple sclerosis and, while its mechanism of action is unclear, it possesses anti-inflammatory and anti-oxidant properties and also impacts on cell metabolism. Here we treated 16-18-month-old female and male mice with DMF for 1 month and assessed its effect on microglia. The evidence indicates that it exerted sex-specific effects on microglial morphology and metabolism, reducing glycolysis only in microglia from female mice. The data suggest that this may result from its ability to inactivate glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
MeSH term(s)	Animals ; Dimethyl Fumarate/metabolism ; Female ; Inflammation/metabolism ; Inflammation Mediators/metabolism ; Male ; Mice ; Microglia/metabolism ; Multiple Sclerosis, Relapsing-Remitting/metabolism
Chemical Substances	Inflammation Mediators ; Dimethyl Fumarate (FO2303MNI2)
Language	English
Publishing date	2022-02-18
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/cells11040729
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Article: Sex-Related Microglial Perturbation Is Related to Mitochondrial Changes in a Model of Alzheimer's Disease.

O'Neill, Eoin / Mela, Virginia / Gaban, Aline Sayd / Bechet, Sibylle / McGrath, Aoife / Walsh, Aife / McIntosh, Allison / Lynch, Marina A

Frontiers in cellular neuroscience

2022 Volume 16, Page(s) 939830

Abstract: Many studies implicate microglia in the pathogenesis of Alzheimer's disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators ... ...

Abstract	Many studies implicate microglia in the pathogenesis of Alzheimer's disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators and it is now known that microglia with this secretory phenotype exhibit other adaptations including in their morphology, function, and metabolism. AD, like many neurological disorders, demonstrates a sex bias and recent evidence indicates that the sexual dimorphism in microglial function, which has been recognized for many years in early development, persists into adulthood and aging. Here, we demonstrate sex-related differences in microglia from post mortem tissue of male and female AD patients and a marked increase in the number of dystrophic and rod-shaped microglia in tissue from female AD patients compared with males. Furthermore, there was an increase in iron-laden microglia in tissue from female AD patients and this has been reported to reflect mitochondrial changes. To address this further, we assessed changes in microglia from male and female APP/PS1 mice and demonstrate that iron accumulation in microglia is increased to a greater extent in tissue prepared from females compared with males. This was associated with altered expression of genes coding for proteins that modulate mitochondrial function. The findings suggest that sex-related differences in the severity and perhaps incidence of AD may, at least in part, arise from sexual dimorphism in microglia.
Language	English
Publishing date	2022-07-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2022.939830
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Article ; Online: Mitochondrial Homeostasis in Obesity-related Hypertriglyceridemia.

Mela, Virginia / Ruiz-Limón, Patricia / Balongo, Manuel / Motahari Rad, Hanieh / Subiri-Verdugo, Alba / Gonzalez-Jimenez, Andres / Soler, Rocio / Ocaña, Luis / El Azzouzi, Hamid / Tinahones, Francisco J / Valdivielso, Pedro / Murri, Mora

The Journal of clinical endocrinology and metabolism

2022 Volume 107, Issue 8, Page(s) 2203–2215

Abstract: Context: The prevalence of obesity and hypertriglyceridemia is an alarming worldwide health issue. Mitochondria play a central role in these disorders as they control cell metabolism.: Objective: The aim of the present study was to characterize ... ...

Abstract	Context: The prevalence of obesity and hypertriglyceridemia is an alarming worldwide health issue. Mitochondria play a central role in these disorders as they control cell metabolism. Objective: The aim of the present study was to characterize mitochondrial homeostasis in subcutaneous and visceral adipose tissue (SAT and VAT) in grade III obese patients with and without hypertriglyceridemia. Moreover, this study presents the evaluation of mitochondrial fitness as a marker for hypertriglyceridemia improvement. Patients: Eight control and 12 hypertriglyceridemic (HTG) grade III obese subjects undergoing bariatric surgery were included. Main outcome measures: Anthropometric and biochemical data were obtained before and 3 months after surgery. Mitochondrial homeostasis was evaluated by mitochondrial DNA (mtDNA), gene expression and protein abundance in SAT and VAT. Results: Mitophagy-related gene expression was increased in HTG SAT and VAT, while mitochondrial marker gene expression and mtDNA were decreased, indicating an altered mitochondrial homeostasis in HTG. Mitophagy protein abundance was increased in VAT of those subjects that did not improve their levels of triglycerides after bariatric surgery, whereas mitochondrial protein was decreased in the same tissue. Indeed, triglyceride levels positively correlated with mitophagy-related genes and negatively with mitochondrial content markers. Moreover, mitochondria content and mitophagy markers seem to be significant predictors of hypertriglyceridemia and hypertriglyceridemia remission. Conclusions: Mitochondrial homeostasis of adipose tissue is altered in hypertriglyceridemic patients. At the protein level, mitochondria content and mitophagy are potential markers of hypertriglyceridemia remission in obese patients after bariatric surgery. These results may contribute to the implementation of a clinical approach for personalized medicine.
MeSH term(s)	Biomarkers/metabolism ; DNA, Mitochondrial ; Homeostasis ; Humans ; Hypertriglyceridemia/complications ; Hypertriglyceridemia/genetics ; Hypertriglyceridemia/metabolism ; Intra-Abdominal Fat/metabolism ; Mitochondria/metabolism ; Obesity/complications ; Obesity/epidemiology ; Obesity/surgery ; Subcutaneous Fat/metabolism
Chemical Substances	Biomarkers ; DNA, Mitochondrial
Language	English
Publishing date	2022-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgac332
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Uh III Zs.134: Show issues

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Article ; Online: Exercise-induced re-programming of age-related metabolic changes in microglia is accompanied by a reduction in senescent cells.

Mela, Virginia / Mota, Bibiana C / Milner, Mark / McGinley, Aoife / Mills, Kingston H G / Kelly, Áine M / Lynch, Marina A

Brain, behavior, and immunity

2020 Volume 87, Page(s) 413–428

Abstract: Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial ... ...

Abstract	Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial activation. Recent evidence indicates that inflammatory microglia are glycolytic, driven by an increase in 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), an enzyme that is described as the master regulator of glycolysis. Here we investigated whether microglia from aged animals exhibited a glycolytic signature and whether exercise exerted a modulatory effect on this metabolic profile. Young (4 month-old) and aged (18 month-old) mice were trained for 10 days on a treadmill. One day before sacrifice, animals were assessed in the novel object recognition and the object displacement tests. Animals were sacrificed after the last bout of exercise, microglial cells were isolated, cultured for 5 days and assessed for metabolic profile. Performance in both behavioural tests was impaired in sedentary aged animals and exercise attenuated this age-related effect. A significant increase in glycolysis, glycolytic capacity and PFKFB3 was observed in microglia from aged animals and exercise ameliorated these effects, while it also increased the phagocytic capacity of cells. The senescent markers, β-galactosidase and p16
MeSH term(s)	Aging ; Animals ; Brain/metabolism ; Cellular Reprogramming ; Cellular Senescence ; Glycolysis ; Mice ; Microglia/metabolism ; Phosphofructokinase-2/metabolism ; Physical Conditioning, Animal
Chemical Substances	PFKFB3 protein, mouse (EC 2.7.1.105) ; Phosphofructokinase-2 (EC 2.7.1.105)
Language	English
Publishing date	2020-01-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639219-2
ISSN	1090-2139 ; 0889-1591
ISSN (online)	1090-2139
ISSN	0889-1591
DOI	10.1016/j.bbi.2020.01.012
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Zs.A 2276: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 327: Show issues

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Article ; Online: The Relationship between Depressive Symptoms, Quality of Life and miRNAs 8 Years after Bariatric Surgery.

Mela, Virginia / Agüera, Zaida / Alvarez-Bermudez, Maria D / Martín-Reyes, Flores / Granero, Roser / Sánchez-García, Ana / Oliva-Olivera, Wilfredo / Tomé, Monica / Moreno-Ruiz, Francisco J / Soler-Humanes, Rocío / Fernández-Serrano, Jose L / Sánchez-Gallegos, Pilar / Martínez-Moreno, Jose M / Sancho-Marín, Raquel / Fernández-Aranda, Fernando / García-Fuentes, Eduardo / Tinahones, Francisco J / Garrido-Sánchez, Lourdes

Nutrients

2023 Volume 15, Issue 19

Abstract: 1) Background: There are conflicting results on whether weight loss after bariatric surgery (BS) might be associated with quality of life (QoL)/depressive symptomatology. We aim to determine whether BS outcomes are associated with QoL/depressive ... ...

Abstract	(1) Background: There are conflicting results on whether weight loss after bariatric surgery (BS) might be associated with quality of life (QoL)/depressive symptomatology. We aim to determine whether BS outcomes are associated with QoL/depressive symptomatology in studied patients at the 8-year follow-up after BS, as well as their relationship with different serum proteins and miRNAs. (2) Methods: A total of 53 patients with class III obesity who underwent BS, and then classified into "good responders" and "non-responders" depending on the percentage of excess weight lost (%EWL) 8 years after BS (%EWL ≥ 50% and %EWL < 50%, respectively), were included. Basal serum miRNAs and different proteins were analysed, and patients completed tests to evaluate QoL/depressive symptomatology at 8 years after BS. (3) Results: The good responders group showed higher scores on SF-36 scales of physical functioning, role functioning-physical, role functioning-emotional, body pain and global general health compared with the non-responders. The expression of hsa-miR-101-3p, hsa-miR-15a-5p, hsa-miR-29c-3p, hsa-miR-144-3p and hsa-miR-19b-3p were lower in non-responders. Hsa-miR-19b-3p was the variable associated with the response to BS in a logistic regression model. (4) Conclusions: The mental health of patients after BS is limited by the success of the intervention. In addition, the expression of basal serum miRNAs related to depression/anxiety could predict the success of BS.
MeSH term(s)	Humans ; Quality of Life ; Depression ; MicroRNAs/metabolism ; Bariatric Surgery ; Obesity
Chemical Substances	MicroRNAs
Language	English
Publishing date	2023-09-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15194109
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Article ; Online: Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer's disease.

Guillot-Sestier, Marie-Victoire / Araiz, Ana Rubio / Mela, Virginia / Gaban, Aline Sayd / O'Neill, Eoin / Joshi, Lisha / Chouchani, Edward T / Mills, Evanna L / Lynch, Marina A

Communications biology

2021 Volume 4, Issue 1, Page(s) 711

Abstract: Age and sex are major risk factors in Alzheimer's disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial ... ...

Abstract	Age and sex are major risk factors in Alzheimer's disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 mice and in post-mortem tissue from AD patients. Changes in genes that are indicative of microglial activation were preferentially increased in cells from female APP/PS1 mice and cells from males and females were morphological, metabolically and functionally distinct. Microglia from female APP/PS1 mice were glycolytic and less phagocytic and associated with increased amyloidosis whereas microglia from males were amoeboid and this was also the case in post-mortem tissue from male AD patients, where plaque load was reduced. We propose that the sex-related differences in microglia are likely to explain, at least in part, the sexual dimorphism in AD.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/etiology ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Female ; Gene Expression Regulation ; Glycolysis ; Humans ; Male ; Mice ; Mice, Transgenic ; Microglia/metabolism ; Microglia/pathology ; Sex Factors
Language	English
Publishing date	2021-06-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-021-02259-y
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