scholarly journals Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex

2017 ◽  
Vol 214 (3) ◽  
pp. 681-697 ◽  
Author(s):  
Ebru Ercan ◽  
Juliette M. Han ◽  
Alessia Di Nardo ◽  
Kellen Winden ◽  
Min-Joon Han ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Tissue Growth ◽  
Mechanistic Target Of Rapamycin ◽  
Genetic Deletion ◽  
Oligodendrocyte Development ◽  
Therapeutic Avenue

Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated secretion of connective tissue growth factor (CTGF). We characterize oligodendrocyte maturation both in vitro and in vivo. We find that neuron-specific Tsc1 deletion results in an increase in CTGF secretion that non–cell autonomously stunts oligodendrocyte development and decreases the total number of oligodendrocytes. Genetic deletion of CTGF from neurons, in turn, mitigates the TSC-dependent hypomyelination phenotype. These results show that the mechanistic target of rapamycin (mTOR) pathway in neurons regulates CTGF production and secretion, revealing a paracrine mechanism by which neuronal signaling regulates oligodendrocyte maturation and myelination in TSC. This study highlights the role of mTOR-dependent signaling between neuronal and nonneuronal cells in the regulation of myelin and identifies an additional therapeutic avenue for this disease.

scholarly journals IL1RAP potentiates multiple oncogenic signaling pathways in AML

2018 ◽  
Vol 215 (6) ◽  
pp. 1709-1727 ◽  
Author(s):  
Kelly Mitchell ◽  
Laura Barreyro ◽  
Tihomira I. Todorova ◽  
Samuel J. Taylor ◽  
Iléana Antony-Debré ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Interleukin 1 ◽  
Oncogenic Signaling ◽  
Genetic Deletion ◽  
Mechanistic Basis ◽  
Oncogenic Signaling Pathways ◽  
Receptor Accessory Protein

The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and pro-proliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.

scholarly journals Do We Have a Cure for Tuberous Sclerosis Complex?

2008 ◽  
Vol 8 (6) ◽  
pp. 159-162 ◽  
Author(s):  
Peter B. Crino
Keyword(s):  
Tuberous Sclerosis ◽  
Task Performance ◽  
Mouse Models ◽  
Tuberous Sclerosis Complex ◽  
Protein Function ◽  
Learning Task ◽  
Neurological Manifestations ◽  
Intractable Seizures

The recent development of several mouse models for tuberous sclerosis complex (TSC) provides in vivo systems to test new therapies for the neurological manifestations of TSC. Rapamycin is known to antagonize the effects of loss of TSC protein function in vitro and in mouse TSC models, rapamycin can prevent seizures and improve learning task performance. These findings provide new hope for TSC patients suffering from intractable seizures and possibly, for those with autism and cognitive disabilities.

scholarly journals miR-19b targets pulmonary endothelial syndecan-1 following hemorrhagic shock

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Feng Wu ◽  
Jian-Ying Wang ◽  
Wei Chao ◽  
Carrie Sims ◽  
Rosemary Ann Kozar
Keyword(s):  
Endothelial Dysfunction ◽  
Hemorrhagic Shock ◽  
Human Lung ◽  
Endothelial Glycocalyx ◽  
Post Shock ◽  
Barrier Breakdown ◽  
Therapeutic Avenue

Abstract Hemorrhagic shock results in systemic injury to the endothelium contributing to post-shock morbidity and mortality. The mechanism involves syndecan-1, the backbone of the endothelial glycocalyx. We have shown in a rodent model that lung syndecan-1 mRNA is reduced following hemorrhage, whereas the molecular mechanism underlying the mRNA reduction is not clear. In this study, we present evidence that miR-19b targets syndecan-1 mRNA to downregulate its expression. Our results demonstrate that miR-19b was increased in hemorrhagic shock patients and in-vitro specifically bound to syndecan-1 mRNA and caused its degradation. Further, hypoxia/reoxygenation (H/R), our in vitro hemorrhage model, increased miR-19b expression in human lung microvascular endothelial cells, leading to a decrease in syndecan-1 mRNA and protein. H/R insult and miR-19b mimic overexpression comparably exaggerated permeability and enhanced endothelial barrier breakdown. The detrimental role of miR-19b in inducing endothelial dysfunction was confirmed in vivo. Lungs from mice undergoing hemorrhagic shock exhibited a significant increase in miR-19b and a concomitant decrease in syndecan-1 mRNA. Pretreatment with miR-19b oligo inhibitor significantly decreased lung injury, inflammation, and permeability and improved hemodynamics. These findings suggest that inhibition of miR-19b may be a putative therapeutic avenue for mitigating post shock pulmonary endothelial dysfunction in hemorrhage shock.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Anti-obesity role of Aster glehni extract: in vivo and in vitro effects

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
HM Lee ◽  
TG Ahn ◽  
CW Kim ◽  
HJ An
Keyword(s):  
In Vitro Effects

A Molecular Approach to Immunoscintigraphy: A Study of the T-Antigen Conformation on the Surface of Tumors

1987 ◽  
Vol 26 (01) ◽  
pp. 1-6 ◽  
Author(s):  
S. Selvaraj ◽  
M. R. Suresh ◽  
G. McLean ◽  
D. Willans ◽  
C. Turner ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Tumor Cell ◽  
T Antigen ◽  
Human Carcinomas ◽  
Animal Tumor ◽  
Synthetic Antigens

The role of glycoconjugates in tumor cell differentiation has been well documented. We have examined the expression of the two anomers of the Thomsen-Friedenreich antigen on the surface of human, canine and murine tumor cell membranes both in vitro and in vivo. This has been accomplished through the synthesis of the disaccharide terminal residues in both a and ß configuration. Both entities were used to generate murine monoclonal antibodies which recognized the carbohydrate determinants. The determination of fine specificities of these antibodies was effected by means of cellular uptake, immunohistopathology and immunoscintigraphy. Examination of pathological specimens of human and canine tumor tissue indicated that the expressed antigen was in the β configuration. More than 89% of all human carcinomas tested expressed the antigen in the above anomeric form. The combination of synthetic antigens and monoclonal antibodies raised specifically against them provide us with invaluable tools for the study of tumor marker expression in humans and their respective animal tumor models.

THYROID STIMULATORS AND THYROID STIMULATION

1971 ◽  
Vol 66 (3) ◽  
pp. 558-576 ◽  
Author(s):  
Gerald Burke
Keyword(s):  
Regulatory System ◽  
Control Site ◽  
Thyroid Cell ◽  
Primary Control ◽  
Physico Chemical ◽  
Site Of Action ◽  
Long Acting

ABSTRACT A long-acting thyroid stimulator (LATS), distinct from pituitary thyrotrophin (TSH), is found in the serum of some patients with Graves' disease. Despite the marked physico-chemical and immunologic differences between the two stimulators, both in vivo and in vitro studies indicate that LATS and TSH act on the same thyroidal site(s) and that such stimulation does not require penetration of the thyroid cell. Although resorption of colloid and secretion of thyroid hormone are early responses to both TSH and LATS, available evidence reveals no basic metabolic pathway which must be activated by these hormones in order for iodination reactions to occur. Cyclic 3′, 5′-AMP appears to mediate TSH and LATS effects on iodination reactions but the role of this compound in activating thyroidal intermediary metabolism is less clear. Based on the evidence reviewed herein, it is suggested that the primary site of action of thyroid stimulators is at the cell membrane and that beyond the(se) primary control site(s), there exists a multifaceted regulatory system for thyroid hormonogenesis and cell growth.

THE ROLE OF POLYETHYLENIMINE IN ENHANCING PERFORMANCE OF GLUTAMATE BIOSENSORS

2018 ◽  
Vol 8 (3) ◽  
pp. 36-41
Author(s):  
Diep Do Thi Hong ◽  
Duong Le Phuoc ◽  
Hoai Nguyen Thi ◽  
Serra Pier Andrea ◽  
Rocchitta Gaia
Keyword(s):  
First Generation ◽  
Good Reproducibility ◽  
Complex Matrices ◽  
Long Term Stability ◽  
In Vitro Characterization ◽  
Glutamate Oxidase

Background: The first biosensor was constructed more than fifty years ago. It was composed of the biorecognition element and transducer. The first-generation enzyme biosensors play important role in monitoring neurotransmitter and determine small quantities of substances in complex matrices of the samples Glutamate is important biochemicals involved in energetic metabolism and neurotransmission. Therefore, biosensors requires the development a new approach exhibiting high sensibility, good reproducibility and longterm stability. The first-generation enzyme biosensors play important role in monitoring neurotransmitter and determine small quantities of substances in complex matrices of the samples. The aims of this work: To find out which concentration of polyethylenimine (PEI) exhibiting the most high sensibility, good reproducibility and long-term stability. Methods: We designed and developed glutamate biosensor using different concentration of PEI ranging from 0% to 5% at Day 1 and Day 8. Results: After Glutamate biosensors in-vitro characterization, several PEI concentrations, ranging from 0.5% to 1% seem to be the best in terms of VMAX, the KM; while PEI content ranging from 0.5% to 1% resulted stable, PEI 1% displayed an excellent stability. Conclusions: In the result, PEI 1% perfomed high sensibility, good stability and blocking interference. Furthermore, we expect to develop and characterize an implantable biosensor capable of detecting glutamate, glucose in vivo. Key words: Glutamate biosensors, PEi (Polyethylenimine) enhances glutamate oxidase, glutamate oxidase biosensors

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