STEM-18. STROMAL EXTRACELLULAR VESICLES DRIVE GLIOMA STEM CELL REPROGRAMMING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi24-vi25
Author(s):  
Lata Adnani ◽  
Brian Meehan ◽  
Jordan Kassouf ◽  
Cristiana Spinelli ◽  
Nadim Tawil ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Extracellular Vesicle ◽  
Host Cells ◽  
Tumour Mass ◽  
Membrane Structures ◽  
And Function ◽  
Rate Limiting ◽  
The Brain

Abstract Glioblastoma multiforme (GBM) represents the most frequent and lethal form of brain tumors originating from glioma stem cells (GSCs). GBM remains lethal because the rate limiting patho-mechanisms remain poorly understood. In this regard, few limitations involve the diversity 'between' cellular states and the molecular/cellular complexity 'within' the tumour mass. Using cell based- and mouse- models, we explored extracellular vesicle (EV) mediated interactions between cancer and stromal cells impacting phenotypes of GSCs as a function of their molecular subtype. EVs are spherical membrane structures that cells release to expel different molecular cargo (lipids, proteins, RNA, DNA), which can be transported across a distance in the brain and taken up by various ‘recipient’ cells resulting in reprogramming of the recipient cell's content and function. In vivo, GSCs altered their pattern of NOTCH signalling and molecular phenotype as a function of proximity to non-transformed host cells in the brain. In vitro stromal EVs altered GSC sphere forming capacity, proteome and expression of mesenchymal markers. Thus, EV mediated tumour-stromal interactions could represent a biological switch and a novel targeting point in the biology of GBM.

scholarly journals DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1

2019 ◽  
Vol 116 (50) ◽  
pp. 25322-25328 ◽  
Author(s):  
Yi Liu ◽  
Xiaopin Ma ◽  
Hisashi Fujioka ◽  
Jun Liu ◽  
Shengdi Chen ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Cellular Mechanism ◽  
Loss Of Function ◽  
Wild Type ◽  
Calcium Efflux ◽  
And Function ◽  
The Brain ◽  
Early Onset Parkinson’S Disease

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.

scholarly journals Astrocytes donate mitochondria to increase glioblastoma tumorigenicity

2021 ◽  
Author(s):  
Justin Lathia ◽  
Dionysios Watson ◽  
Defne Bayik ◽  
Sarah Williford ◽  
Adam Lauko ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cell Communication ◽  
Treatment Resistance ◽  
Extracellular Vesicle ◽  
Host Cells ◽  
Molecular Events ◽  
Mitochondrial Transfer ◽  
New Research

Abstract Glioblastoma (GBM), the most common primary brain cancer in adults1, is characterized by numerous cell-intrinsic/extrinsic interactions that drive tumorigenesis. In addition to cell-surface and secreted protein/extracellular vesicle interactions2,3, treatment resistance of GBM is augmented by the formation of cytoplasmic interconnections and junctions among tumor cells4. These cytoplasmic bridges among tumor cells enable exchange of cellular metabolites as well as mitochondria4, which can play a key role in metabolic function and cellular programming in GBM5,6. However, the contribution of the tumor microenvironment to mitochondrial transfer, as well as the downstream impact of mitochondrial transfer on GBM remains poorly characterized. Here we identified horizontal mitochondrial transfer from the tumor microenvironment as a mechanism that enhances tumorigenesis in glioblastoma. We found that this transfer occurs primarily from brain-resident cells, including astrocytes, and can be appreciated in vitro and in vivo through intercellular connections between GBM cells and non-malignant host cells. The acquisition of astrocyte mitochondria drives an overall enhancement of mitochondrial membrane potential and metabolic capacity, while increasing glioblastoma cell self-renewal and tumor-initiating capacity. Collectively, our findings demonstrate that astrocyte mitochondrial transfer augments the tumorigenic capacity of glioblastoma cells and reveals a previously unknown cell-cell communication mechanism that drives tumor growth. We anticipate our findings will open new research directions to decipher the molecular events linking mitochondria acquisition from non-malignant cells to increased tumorigenicity of recipient GBM cells. This line of research will lead to new therapeutic opportunities targeting this understudied phenomenon and its sequelae in GBM.

scholarly journals HAEMOLYMPH AND TISSUE TITRES OF ACHETAKININS IN THE HOUSE CRICKET ACHETA DOMESTICUS: EFFECT OF STARVATION AND DEHYDRATION

1994 ◽  
Vol 193 (1) ◽  
pp. 307-319 ◽  
Author(s):  
J Chung ◽  
G Goldsworthy ◽  
G Coast
Keyword(s):  
Acheta Domesticus ◽  
High Concentration ◽  
House Cricket ◽  
Immunoreactive Material ◽  
Access To Water ◽  
And Function ◽  
Thoracic And Abdominal ◽  
The Brain

Achetakinin-like immunoreactive material in tissues and haemolymph of adult male crickets was quantified by radioimmunoassay. Achetakinin-like material was found in the brain, suboesophageal ganglia and the thoracic and abdominal ganglia, but the largest amount was within the retrocerebral complex. A Ca2+-dependent release of achetakinin-like immunoreactive material was demonstrated from retrocerebral complexes incubated in vitro in saline containing a high concentration of K+. The concentration of achetakinin-like material in haemolymph from fed crickets was estimated to be 2.8 nmol l-1 and increased more than 10-fold in insects starved for 48 h without access to water. The presence of achetakinin-like material in haemolymph suggests that these peptides are released in vivo and function as circulating neurohormones.

scholarly journals The Significance of Anoxæmia in Modern Psychiatric Treatment

1939 ◽  
Vol 32 (8) ◽  
pp. 951-958 ◽  
Author(s):  
J. H. Quastel
Keyword(s):  
Nervous System ◽  
Glucose Oxidation ◽  
Psychiatric Treatment ◽  
Venous Blood ◽  
In Vivo Studies ◽  
Venous Blood Flow ◽  
And Function ◽  
The Brain

Blood in its passage through the brain loses oxygen and glucose at relatively high rates, the amount of oxygen disappearing being approximately equivalent to the amount of glucose consumed, calculating on the basis that the sugar is completely oxidized. The respiratory quotient of brain in vivo is unity. These facts point to the dominance of carbohydrate oxidation in brain respiration in vivo and are similar to those found in studies of brain in vitro. Various factors influence glucose oxidation in brain, e.g. changes in the ionic environment of the cells, vitamin B1, or the presence of narcotics. The latter bring about inhibitions of glucose oxidation in brain tissue which may in most cases be shown to be reversible in vitro. Glucose is not only important for the maintenance of respiration of brain but for enabling certain synthetic processes to occur. One of these is the formation of acetylcholine whose physiological significance is now well known and whose synthesis seems to be confined to the nervous system. This synthesis depends not only on the presence of glucose but on that of oxygen. The influence of glucose has been observed also in investigations on cortical potentials. An important feature of the nerve cell is its vulnerability to the lack of oxygen. Reversibility depends on the degree and duration of the anoxæmia. During insulin shock treatment studies of brain in vivo show lowered oxygen consumption and glucose utilization, these depending on the degree of hypoglycæmia. In cardiazol treatment, in vivo studies show that the oxygen content of the blood may fall to 42%. During the convulsion there is a greatly lowered arterial and venous blood-flow through the brain and cerebral anæmia becomes a marked feature. In narcosis treatment both in vitro and in vivo studies show a diminished ability of the brain to consume oxygen. It is suggested that the most significant facts to be taken into account are (1) the importance of glucose and oxygen for the metabolism and function of the nervous system, (2) the vulnerability and varying sensitivities of nerve cells to lack of oxygen and glucose, (3) the occurrence of varying degrees of cerebral anoxæmia in narcosis, insulin and cardiazol treatments.

scholarly journals Bone degradation machinery of osteoclasts: An HIV-1 target that contributes to bone loss

2018 ◽  
Vol 115 (11) ◽  
pp. E2556-E2565 ◽  
Author(s):  
Brigitte Raynaud-Messina ◽  
Lucie Bracq ◽  
Maeva Dupont ◽  
Shanti Souriant ◽  
Shariq M. Usmani ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Bone Defects ◽  
Host Cells ◽  
Bone Degradation ◽  
Sealing Zone ◽  
And Function ◽  
Human Osteoclasts ◽  
Hiv 1

Bone deficits are frequent in HIV-1–infected patients. We report here that osteoclasts, the cells specialized in bone resorption, are infected by HIV-1 in vivo in humanized mice and ex vivo in human joint biopsies. In vitro, infection of human osteoclasts occurs at different stages of osteoclastogenesis via cell-free viruses and, more efficiently, by transfer from infected T cells. HIV-1 infection markedly enhances adhesion and osteolytic activity of human osteoclasts by modifying the structure and function of the sealing zone, the osteoclast-specific bone degradation machinery. Indeed, the sealing zone is broader due to F-actin enrichment of its basal units (i.e., the podosomes). The viral protein Nef is involved in all HIV-1–induced effects partly through the activation of Src, a regulator of podosomes and of their assembly as a sealing zone. Supporting these results, Nef-transgenic mice exhibit an increased osteoclast density and bone defects, and osteoclasts derived from these animals display high osteolytic activity. Altogether, our study evidences osteoclasts as host cells for HIV-1 and their pathological contribution to bone disorders induced by this virus, in part via Nef.

scholarly journals Fractal dimension and neurotoxicity in rats intoxicated by aluminium

2015 ◽  
Vol 69 (1-2) ◽  
pp. 21-29
Author(s):  
Ljiljana Martac
Keyword(s):  
Animal Model ◽  
Spectral Power ◽  
Brain Activity ◽  
Aluminium Toxicity ◽  
Experimental Models ◽  
Mathematical Methods ◽  
And Function ◽  
The Brain

We used animal model of neurotoxicity in rats, which provided the possibility of studying biological pathophysiological phenomena in vivo and afterwards in vitro conditions. The analysis of electrocortical brain activity using mathematical methods can describe the changes induced by aluminum intoxication in rat as an animal model. In physiological and pathophysiological conditions, on experimental models, mechanisms related to changes in behavior, plasticity and accumulation of aluminum in nervous tissue of the rat brain were observed. Animal models of rats used in the experiments described changes in the group of neuronal activity in the brain of rats in different modes of intoxication aluminum. This study describes ECoG activity in the brain of rats under anesthesia in both the control and aluminum treated animals. Fractal and spectral analysis was used to present qualitative and quantitative changes in the conditions of neurotoxicity. Changes in neurotransmission, as well as the structure and function of the neural network are connected to the molecular-physiological mechanisms of neurotoxicity. Aluminium toxicity was monitored through changes in glutamatergic activity and calcium channel activity. By spectrum analysis neurotoxicity was described through changes in spectral power in the corresponding frequency ranges. By comparing the FD of intoxicated and control individuals there was obtained the range of the change in correlation with the corresponding pathophysiological conditions of intoxication. The shange in FD might be an indication of neurotoxicity.

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.

Novel Phospholipid-Based Labrasol Nanomicelles Loaded Flavonoids for Oral Delivery with Enhanced Penetration and Anti-Brain Tumor Efficiency

2020 ◽  
Vol 17 (3) ◽  
pp. 229-245
Author(s):  
Gang Wang ◽  
Junjie Wang ◽  
Rui Guan
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Oral Delivery ◽  
Safe Delivery ◽  
Drug Delivery Vehicles ◽  
Therapeutic Benefits ◽  
Delivery Vehicles ◽  
The Brain

Background: Owing to the rich anticancer properties of flavonoids, there is a need for their incorporation into drug delivery vehicles like nanomicelles for safe delivery of the drug into the brain tumor microenvironment. Objective: This study, therefore, aimed to prepare the phospholipid-based Labrasol/Pluronic F68 modified nano micelles loaded with flavonoids (Nano-flavonoids) for the delivery of the drug to the target brain tumor. Methods: Myricetin, quercetin and fisetin were selected as the initial drugs to evaluate the biodistribution and acute toxicity of the drug delivery vehicles in rats with implanted C6 glioma tumors after oral administration, while the uptake, retention, release in human intestinal Caco-2 cells and the effect on the brain endothelial barrier were investigated in Human Brain Microvascular Endothelial Cells (HBMECs). Results: The results demonstrated that nano-flavonoids loaded with myricetin showed more evenly distributed targeting tissues and enhanced anti-tumor efficiency in vivo without significant cytotoxicity to Caco-2 cells and alteration in the Trans Epithelial Electric Resistance (TEER). There was no pathological evidence of renal, hepatic or other organs dysfunction after the administration of nanoflavonoids, which showed no significant influence on cytotoxicity to Caco-2 cells. Conclusion: In conclusion, Labrasol/F68-NMs loaded with MYR and quercetin could enhance antiglioma effect in vitro and in vivo, which may be better tools for medical therapy, while the pharmacokinetics and pharmacodynamics of nano-flavonoids may ensure optimal therapeutic benefits.

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