scholarly journals Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology

2018 ◽  
Vol 115 (45) ◽  
pp. 11625-11630 ◽  
Author(s):  
María Díaz-Moreno ◽  
Tomás Armenteros ◽  
Simona Gradari ◽  
Rafael Hortigüela ◽  
Laura García-Corzo ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Late Onset ◽  
Hippocampal Neurogenesis ◽  
Bmp Signaling ◽  
In Vitro Assays ◽  
Age Related ◽  
Samp8 Mice ◽  
The Brain

Increasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer’s disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a nontransgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation. In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway and its progliogenic effect in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain’s natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.

TMOD-31. AN ORGANOTYPIC TISSUE PLATFORM TO BRIDGE IN VITRO AND IN VIVO ASSAYS FOR BRAIN CANCER TREATMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi222-vi222
Author(s):  
Breanna Mann ◽  
Noah Bell ◽  
Denise Dunn ◽  
Scott Floyd ◽  
Shawn Hingtgen ◽  
...  
Keyword(s):  
Cell Lines ◽  
Brain Cancer ◽  
Brain Slice ◽  
Brain Slices ◽  
In Vitro Assays ◽  
Preclinical Model ◽  
Short Period ◽  
The Brain

Abstract Brain cancers remain one of the greatest medical challenges. The lack of experimentally tractable models that recapitulate brain structure/function represents a major impediment. Platforms that enable functional testing in high-fidelity models are urgently needed to accelerate the identification and translation of therapies to improve outcomes for patients suffering from brain cancer. In vitro assays are often too simple and artificial while in vivo studies can be time-intensive and complicated. Our live, organotypic brain slice platform can be used to seed and grow brain cancer cell lines, allowing us to bridge the existing gap in models. These tumors can rapidly establish within the brain slice microenvironment, and morphologic features of the tumor can be seen within a short period of time. The growth, migration, and treatment dynamics of tumors seen on the slices recapitulate what is observed in vivo yet is missed by in vitro models. Additionally, the brain slice platform allows for the dual seeding of different cell lines to simulate characteristics of heterogeneous tumors. Furthermore, live brain slices with embedded tumor can be generated from tumor-bearing mice. This method allows us to quantify tumor burden more effectively and allows for treatment and retreatment of the slices to understand treatment response and resistance that may occur in vivo. This brain slice platform lays the groundwork for a new clinically relevant preclinical model which provides physiologically relevant answers in a short amount of time leading to an acceleration of therapeutic translation.

scholarly journals Physicochemical Characterization and Biological Activities of Black and White Garlic: In Vivo and In Vitro Assays

Foods ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 220 ◽  
Author(s):  
María Ángeles Toledano Medina ◽  
Tania Merinas-Amo ◽  
Zahira Fernández-Bedmar ◽  
Rafael Font ◽  
Mercedes del Río-Celestino ◽  
...  
Keyword(s):  
Antioxidant Capacity ◽  
Genetic Model ◽  
Biological Activities ◽  
Leukemia Cell ◽  
Physicochemical Characterization ◽  
Biological Data ◽  
In Vitro Assays ◽  
Age Related

White and three types of black garlic (13, 32, and 45 days of aging, named 0C1, 1C2, and 2C1, respectively) were selected to study possible differences in their nutraceutic potential. For this purpose, garlic were physicochemically characterized (Brix, pH, aW, L, polyphenol, and antioxidant capacity), and both in vivo and in vitro assays were carried out. Black garlic samples showed higher polyphenol content and antioxidant capacity than the white ones. The biological assays showed that none of the samples (neither raw nor black garlic) produced toxic effects in the Drosophila melanogaster animal genetic model, nor exerted protective effects against H2O2, with the exception of the 0C1 black garlic. Moreover, only white garlic was genotoxic at the highest concentration. On the other hand, 0C1 black garlic was the most antigenotoxic substance. The in vivo longevity assays showed significant extension of lifespan at some concentrations of white and 0C1and 1C2 black garlic. The in vitro experiments showed that all of the garlic samples induced a decrease in leukemia cell growth. However, no type of garlic was able to induce proapoptotic internucleosomal DNA fragmentation. Taking into account the physicochemical and biological data, black garlic could be considered a potential functional food and used in the preventive treatment of age-related diseases. In addition, our findings could be relevant for black-garlic-processing agrifood companies, as the economical and timing costs can significantly be shortened from 45 to 13 days of aging.

scholarly journals Leveraging Nuclear Receptors as Targets for Pathological Ocular Vascular Diseases

2020 ◽  
Vol 21 (8) ◽  
pp. 2889 ◽  
Author(s):  
Pei-Li Yao ◽  
Jeremy Peavey ◽  
Goldis Malek
Keyword(s):  
Nuclear Receptors ◽  
Vascular Diseases ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
In Vitro Assays ◽  
In Vivo Models ◽  
Age Related ◽  
Vessel Growth

Vasculogenesis and angiogenesis are physiological mechanisms occurring throughout the body. Any disruption to the precise balance of blood vessel growth necessary to support healthy tissue, and the inhibition of abnormal vessel sprouting has the potential to negatively impact stages of development and/or healing. Therefore, the identification of key regulators of these vascular processes is critical to identifying therapeutic means by which to target vascular-associated compromises and complications. Nuclear receptors are a family of transcription factors that have been shown to be involved in modulating different aspects of vascular biology in many tissues systems. Most recently, the role of nuclear receptors in ocular biology and vasculopathies has garnered interest. Herein, we review studies that have used in vitro assays and in vivo models to investigate nuclear receptor-driven pathways in two ocular vascular diseases associated with blindness, wet or exudative age-related macular degeneration, and proliferative diabetic retinopathy. The potential therapeutic targeting of nuclear receptors for ocular diseases is also discussed.

scholarly journals Modulation of Hippocampal Astroglial Activity by Synaptamide in Rats with Neuropathic Pain

2021 ◽  
Vol 11 (12) ◽  
pp. 1561
Author(s):  
Igor Manzhulo ◽  
Olga Manzhulo ◽  
Anna Tyrtyshnaia ◽  
Arina Ponomarenko ◽  
Sophia Konovalova ◽  
...  
Keyword(s):  
Chronic Constriction Injury ◽  
Hippocampal Neurogenesis ◽  
Liquid Chromatography Mass Spectrometry ◽  
Cold Allodynia ◽  
In Vivo Experiments ◽  
Mass Spectrometry Technique ◽  
Spectrometry Technique ◽  
The Brain

The present study demonstrates that synaptamide (N-docosahexaenoylethanolamine), an endogenous metabolite of docosahexaenoic acid, when administered subcutaneously (4 mg/kg/day, 14 days), exhibits analgesic activity and promotes cognitive recovery in the rat sciatic nerve chronic constriction injury (CCI) model. We analyzed the dynamics of GFAP-positive astroglia and S100β-positive astroglia activity, the expression of nerve growth factor (NGF), and two subunits of the NMDA receptor (NMDAR1 and NMDAR2A) in the hippocampi of the experimental animals. Hippocampal neurogenesis was evaluated by immunohistochemical detection of DCX. Analysis of N-acylethanolamines in plasma and in the brain was performed using the liquid chromatography-mass spectrometry technique. In vitro and in vivo experiments show that synaptamide (1) reduces cold allodynia, (2) improves working memory and locomotor activity, (3) stabilizes neurogenesis and astroglial activity, (4) enhances the expression of NGF and NMDAR1, (5) increases the concentration of Ca2+ in astrocytes, and (6) increases the production of N-acylethanolamines. The results of the present study demonstrate that synaptamide affects the activity of hippocampal astroglia, resulting in faster recovery after CCI.

scholarly journals Identification, Expression, and Roles of the Cystine/Glutamate Antiporter in Ocular Tissues

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Renita M. Martis ◽  
Luis J. Knight ◽  
Paul J. Donaldson ◽  
Julie C. Lim
Keyword(s):  
Knockout Mouse ◽  
Redox Balance ◽  
Ocular Tissues ◽  
Age Related ◽  
Neural Tissues ◽  
The Brain ◽  
Oxidative State ◽  
Shed Light

The cystine/glutamate antiporter (system xc-) is composed of a heavy chain subunit 4F2hc linked by a disulphide bond to a light chain xCT, which exchanges extracellular cystine, the disulphide form of the amino acid cysteine, for intracellular glutamate. In vitro research in the brain, kidney, and liver have shown this antiporter to play a role in minimising oxidative stress by providing a source of intracellular cysteine for the synthesis of the antioxidant glutathione. In vivo studies using the xCT knockout mouse revealed that the plasma cystine/cysteine redox couple was tilted to a more oxidative state demonstrating system xc- to also play a role in maintaining extracellular redox balance by driving a cystine/cysteine redox cycle. In addition, through import of cystine, system xc- also serves to export glutamate into the extracellular space which may influence neurotransmission and glutamate signalling in neural tissues. While changes to system xc- function has been linked to cancer and neurodegenerative disease, there is limited research on the roles of system xc- in the different tissues of the eye, and links between the antiporter, aging, and ocular disease. Hence, this review seeks to consolidate research on system xc- in the cornea, lens, retina, and ocular humours conducted across several species to shed light on the in vitro and in vivo roles of xCT in the eye and highlight the utility of the xCT knockout mouse as a tool to investigate the contribution of xCT to age-related ocular diseases.

scholarly journals L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

2017 ◽  
Vol 37 (8) ◽  
Author(s):  
Shenghong Ma ◽  
Renqiang Sun ◽  
Bowen Jiang ◽  
Jun Gao ◽  
Wanglong Deng ◽  
...  
Keyword(s):  
White Matter ◽  
Histone Methylation ◽  
Autosomal Recessive ◽  
Late Onset ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Oligodendrocyte Progenitor Cells ◽  
The Brain ◽  
Hg Accumulation

ABSTRACT l -2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the l -2-hydroxyglutarate dehydrogenase ( L2HGDH ) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of l -2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.

scholarly journals Physico-Chemical Characterization and Biological Activities of Black and White Garlic: In Vivo and In Vitro Assays

2019 ◽  
Author(s):  
Mª Ángeles Toledano Medina ◽  
Tania Merinas-Amo ◽  
Zahira Fernández-Bedmar ◽  
Rafael Font ◽  
Mercedes del Río-Celestino ◽  
...  
Keyword(s):  
Biological Activities ◽  
Chemical Characterization ◽  
Preventive Treatment ◽  
Biological Data ◽  
In Vitro Assays ◽  
Protective Effects ◽  
Age Related ◽  
Biological Studies

White and three types of black garlic (13, 32 and 45 days of fermentation, named 0C1, 1C2 and 2C1 respectively) were selected in order to check possible differences in their nutraceutic potential. For this purpose, garlic were physico-chemically characterised, and both in vivo and in vitro assays were carried out. Black garlic showed higher polyphenol content and antioxidant capacity than white garlic. The biological studies have shown that only white garlic was not safe showing toxicity effect. Furthermore, none garlic exert protective effects against H2O2, except the 0C1 black garlic. Moreover, garlic was non-genotoxic with the exception of the highest concentration of white garlic. On the other hand, 0C1 was the most antigenotoxic substance. The in vivo longevity assays yielded significant extension of lifespan results in some concentrations of white and 0C1and 1C2 black garlic. The in vitro experiments showed that all studied garlic induced a decrease in leukaemia cells growth. However, none type of garlic was able to induce proapoptotic internucleosomal DNA fragmentation. Taking into account the physicochemical and biological data, black garlic could be considered as a potential functional food and used in preventive treatment of age-related diseases. In addition, our findings could be relevant for the black garlic processing agrifood companies as the economical and timing costs are significantly reduced to 13 days aging.

Evaluation of TNF-α/Bax Gene Therapy and Radiation against C6 Glioma Xenografts

2003 ◽  
Vol 2 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Daila S. Gridley ◽  
Tatyana M. Timiryasova ◽  
Glen M. Miller ◽  
Melba L. Andres ◽  
Radha Dutta-Roy ◽  
...  
Keyword(s):  
Gene Therapy ◽  
C6 Glioma ◽  
In Vitro Assays ◽  
Bax Protein ◽  
Treatment Type ◽  
Tnf Α ◽  
Bax Gene ◽  
The Brain

Successful therapy of high-grade tumors of the brain is likely to require a combination of new therapeutic approaches. The major goal of the present study was to construct a plasmid-based bax gene vector (pGL1-Bax) and evaluate its expression in vitro and in vivo using athymic mice with subcutaneously growing C6 glioma. Preliminary experiments of efficacy and safety were also performed using pGL1-Bax alone and in combination with previously constructed pGL1-TNF-α, as well as with radiation. pGL1-Bax was expressed by C6 cells and was correlated with apoptosis, indicating that the construct and the bax protein were functional. Although intratumoral injections of pGL1-Bax alone, up to total doses of 450 μg, did not significantly affect tumor growth, consistently smaller tumors were obtained when pGL1-TNF-α plus pGL1-Bax were injected 16–18 hr prior to tumor irradiation. Furthermore, in mice with two tumors, one treated and one untreated, progression of the untreated tumor was delayed in the animals receiving all three modalities. No prohibitive toxicities were noted, based on mouse body weights and in vitro assays of blood and spleen. Significant increases in spleen mass, total leukocyte counts, percentage of granulocytes, spontaneous blastogenesis, and CD71-expressing B cells were primarily associated with tumor presence and not treatment type. Overall, the results are promising and suggest that TNF-α/Bax gene therapy may be beneficial against highly malignant tumors of the brain. To our knowledge, this is the first report of bax gene therapy used together with radiation in an in vivo glioma model.

scholarly journals Palm Fruit Bioactive Complex (PFBc), a Source of Polyphenols, Demonstrates Potential Benefits for Inflammaging and Related Cognitive Function

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1127
Author(s):  
Susan J. Hewlings ◽  
Kristin Draayer ◽  
Douglas S. Kalman
Keyword(s):  
Gene Expression ◽  
Cognitive Function ◽  
Cognitive Decline ◽  
Healthy Aging ◽  
Elaeis Guineensis ◽  
Palm Fruit ◽  
Age Related ◽  
Anti Inflammatory

Cognitive function is a key aspect of healthy aging. Inflammation associated with normal aging, also called inflammaging is a primary risk factor for cognitive decline. A diet high in fruits and vegetable and lower in calories, particularly a Mediterranean Diet, may lower the risk of age-related cognitive decline due in part to the associated high intake of antioxidants and polyphenols. A phenolic, Palm Fruit Bioactive complex (PFBc) derived from the extraction process of palm oil from oil palm fruit (Elaeis guineensis), is reported to offset inflammation due to its high antioxidant, especially vitamin E, and polyphenol content. The benefit is thought to be achieved via the influence of antioxidants on gene expression. It is the purpose of this comprehensive review to discuss the etiology, including gene expression, of mild cognitive impairment (MCI) specific to dietary intake of antioxidants and polyphenols and to focus on the potential impact of nutritional interventions specifically PFBc has on MCI. Several in vitro, in vivo and animal studies support multiple benefits of PFBc especially for improving cognitive function via anti-inflammatory and antioxidant mechanisms. While more human studies are needed, those completed thus far support the benefit of consuming PFBc to enhance cognitive function via its anti-inflammatory antioxidant functions.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

Sign in / Sign up

Export Citation Format

Share Document