TAMI-21. TUMOR-ASSOCIATED MICROGLIA GUIDE GBM INFILTRATION VIA PLEXIN-B2

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi202-vi202
Author(s):  
Sangjo Kang ◽  
Anirudh Sattiraju ◽  
Yuhuan Li ◽  
Shalaka Wahane ◽  
Theo Hanna ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Close Contact ◽  
Primary Brain Tumor ◽  
Physical Interaction ◽  
Wide Field ◽  
Cell Alignment ◽  
Ecm Remodeling ◽  
Underlying Mechanisms ◽  
Cellular Alignment ◽  
The Brain

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor. The nature of invasiveness of GBM makes complete surgical resection difficult. However, how GBM cells achieve wide infiltration in the brain is poorly understood. Microglia, the resident immune cells in the brain can support GBM growth and invasion, but the underlying mechanisms remain elusive. Here, we show that microglia are activated in a wide field away from tumor boundaries, ahead of tumor cell infiltration. Invading GBM cells are in close contact with microglia, progressively aligned with one another in the direction of tumor invasion. Moreover, ECM is also aligned with the infiltrating tumor and microglia, which may serve as invasion tracks in the brain. Mechanistically, we demonstrate that microglia direct cellular alignment and ECM remodeling in the invasion tracks through an axon guidance receptor Plexin-B2. Myeloid-specific ablation of Plexin-B2 perturbs microglia and tumor cell alignment, microglia migration, ECM organization, and GBM invasiveness. Together, our data reveal a hitherto under-appreciated role of microglia in providing directional cues for GBM invasion through physical interaction and alignment of ECM and tumor cells, thus providing new insights and novel molecular targets in curbing GBM invasion.

New Spirocyclic Hydroxamic Acids as Effective Antiproliferative Agents

2020 ◽  
Vol 20 ◽  
Author(s):  
Margarita E. Neganova ◽  
Sergey G. Klochkov ◽  
Yulia R. Aleksandrova ◽  
Vladimir N. Osipov ◽  
Dmitry V. Avdeev ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Antioxidant Activities ◽  
Hydroxamic Acids ◽  
Cytotoxic Activities ◽  
Tumor Cell Lines ◽  
Hek 293 ◽  
Underlying Mechanisms

Aims: The main goal of this work where is to synthesize new original spirocyclic hydroxamic acids, investigate their cytotoxicity against to the panel of tumor cell lines and possible mechanism of action of these active compounds. Background: Hydroxamic acids are one of the promising classes of chemical compounds with proven has anticancer potential properties. This is manifested in the presence of metal chelating and antioxidant activities, the ability to inhibit histone deacetylase enzymes and a chemosensitizing effect against well known cytostatics. Objective: Original spirocyclic hydroxamic acids were synthesized and spectrums of their antiproliferative activities were investigated. Methods: The cytotoxic activities on different tumor lines (SH-SY5Y, HeLa and healthy cells HEK-293) were investigated and determined possible underlying mechanisms of their activity. Result: New original spirocyclic hydroxamic acids were synthesized. These compounds exhibit antiproliferative properties against of the various tumor cultures cells and also exhibits antioxidant activity, a depolarizing effect on the mitochondrial membrane, inhibit the activity of the histone deacetylase enzyme, and also decrease of basal glycolysis and glycolytic capacity reserve of HeLa and SH-SY5Y tumor cell lines. Conclusion: The most promising are compounds 5j-l containing two chlorine atoms as substituents in the quinazoline part of the molecule and hydroxamate function. Therefore, these compounds can be considered as hit compounds for the development on their basis multi-target anticancer agents.

Minocycline inhibits mTOR signaling activation and alleviates behavioral deficits in the Wistar rats with acute ischemia stroke

2020 ◽  
Vol 19 ◽  
Author(s):  
Shengyuan Wang ◽  
Chuanling Wang ◽  
Lihua Wang ◽  
Zhiyou Cai
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Acute Ischemia ◽  
Intragastric Administration ◽  
Underlying Mechanisms ◽  
Signaling Activation ◽  
The Brain ◽  
Minocycline Therapy

Background: Mammalian target of rapamycin (mTOR) has been evidenced as a multimodal therapy in the path-ophysiological process of acute ischemic stroke (AIS). However, the pathway that minocycline targets mTOR signaling is not fully defined in the AIS pathogenesis. This study is to aim at the effects of minocycline on the mTOR signaling in the AIS process and further discover the underlying mechanisms of minocycline involved in the following change of mTOR signaling-autophagy. Methods: Cerebral ischemia/reperfusion (CIR) rat animal models were established with the transient suture occlusion into middle cerebral artery. Minocycline (50mg/kg) was given by intragastric administration. The Morris water maze was used to test the cognitive function of animals. Immunohistochemistry and immunofluorescence were introduced for testing the lev-els of synaptophysin and PSD-95. Western blot was conducted for investigating the levels of mTOR, p-mTOR (Ser2448), p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366), p-eIF4B (Ser406), LC3, p62, synaptophysin and PSD-95. Results: Minocycline prevents cognitive decline of the MCAO stroke rats. Minocycline limits the expression of p-mTOR (Ser2448) and the downstream targets of mTOR [p70S6, p-p70S6 (Thr389), eEF2k, p-eEF2k (Ser366) and p-eIF4B (Ser406)] (P<0.01), while minocycline has no influence on mTOR. LC3-II abundance and the LC3-II/I ratio were upregu-lated in the hippocampus of the MCAO stroke rats by the minocycline therapy (P<0.01). p62 was downregulated in the hippocampus from the MCAO stroke rats administrated with minocycline therapy(P<0.01). The levels of SYP and PSD-95 were up-regulated in the brain of the MCAO stroke rats administrated with minocycline therapy. Conclusion: Minocycline prevents cognitive deficits via inhibiting mTOR signaling and enhancing autophagy process, and promoting the expression of pre-and postsynaptic proteins (synaptophysin and PSD-95) in the brain of the MCAO stroke rats. The potential neuroprotective role of minocycline in the process of cerebral ischemia may be related to mitigating is-chemia-induced synapse injury via inhibiting activation of mTOR signaling.

scholarly journals Molecular Mechanisms of Drug Resistance in Glioblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6385
Author(s):  
Maya A. Dymova ◽  
Elena V. Kuligina ◽  
Vladimir A. Richter
Keyword(s):  
Drug Resistance ◽  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Therapeutic Resistance ◽  
Molecular Characteristics ◽  
Blood Brain ◽  
Conventional Radiation ◽  
The Brain ◽  
Made In

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB).

scholarly journals The manifold actions of the protein inhibitor of activated STAT proteins on the transcriptional activity of mineralocorticoid and glucocorticoid receptors in neural cells

2004 ◽  
Vol 32 (3) ◽  
pp. 825-841 ◽  
Author(s):  
M Tirard ◽  
J Jasbinsek ◽  
OF Almeida ◽  
TM Michaelidis
Keyword(s):  
Transcriptional Activity ◽  
Glucocorticoid Receptors ◽  
Specific Interaction ◽  
Human Neuroblastoma Cell ◽  
Physical Interaction ◽  
Neural Cells ◽  
Protein Inhibitor ◽  
Human Neuroblastoma ◽  
The Brain ◽  
Two Hybrid

Corticosteroid actions in the brain are exerted via the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). These receptors share several structural and functional similarities but their activation in the brain triggers distinct biological actions, for instance on neuronal survival or the regulation of the hypothalamo-pituitary-adrenal axis. Like other hormone-activated receptors, the transcriptional properties of the MR and GR depend on their ability to recruit a variety of co-regulators, which modulate their activity on target promoters, in a specific manner. The N-terminal regions of the MR and GR share the smallest degree of sequence conservation, whereas they display opposite effects on the transactivation properties of these receptors; thus, they may provide surfaces suitable for receptorspecific interactions with co-regulatory proteins. Here, we employed a yeast two-hybrid system to identify molecules interacting with the N-terminal part of the MR (amino acids 170-433). This approach resulted in the isolation of representative cDNAs from all members of the protein inhibitor of activated STAT (PIAS) family of proteins as potential MR-interacting partners. In neural cells, PIAS3 exhibited a strong and specific interaction with MR, but not GR, as indicated by mammalian two-hybrid assays and co-immunoprecipitation experiments in vivo. The interaction with MR was enhanced in the presence of aldosterone, an MR agonist, and was found to occur through a conserved, serine- and acidic amino acid residue-rich domain of PIAS3. To compare the modulatory properties of PIAS proteins on MR and GR transcriptional activity in a neural environment, MMTV reporter gene assays were performed in the human neuroblastoma cell line SK-N-MC. This analysis revealed that PIAS3 can inhibit MR, but not GR, transactivation in response to their corresponding ligands. Further, it showed that PIAS1 and PIASxbeta, but not PIASy, could also inhibit MR-mediated transcription despite the lack of detected physical interaction with MR. Interestingly, PIASxbeta and PIASy dose-dependently co-activated GR, whereas PIAS1 impaired GR-induced transcription. Taken together the results reveal differential modulatory roles of the PIAS proteins on the transcriptional properties of MR and GR, thus providing new insights into the bifurcating actions of these two receptors in neural cells where they are frequently co-localized.

scholarly journals Ventilation and neurochemical changes during µ-opioid receptor activation or blockade of excitatory receptors in the hypoglossal motor nucleus of goats

2017 ◽  
Vol 123 (6) ◽  
pp. 1532-1544 ◽  
Author(s):  
Thomas M. Langer ◽  
Suzanne E. Neumueller ◽  
Emma Crumley ◽  
Nicholas J. Burgraff ◽  
Sawan Talwar ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Pulmonary Ventilation ◽  
Respiratory Control ◽  
Nrem Sleep ◽  
Receptor Activation ◽  
Motor Nucleus ◽  
Physiological Conditions ◽  
Neurochemical Changes ◽  
Underlying Mechanisms ◽  
The Brain

Neuromodulator interdependence posits that changes in one or more neuromodulators are compensated by changes in other modulators to maintain stability in the respiratory control network. Herein, we studied compensatory neuromodulation in the hypoglossal motor nucleus (HMN) after chronic implantation of microtubules unilaterally ( n = 5) or bilaterally ( n = 5) into the HMN. After recovery, receptor agonists or antagonists in mock cerebrospinal fluid (mCSF) were dialyzed during the awake and non-rapid eye movement (NREM) sleep states. During day studies, dialysis of the µ-opioid inhibitory receptor agonist [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO; 100 µM) decreased pulmonary ventilation (V̇i), breathing frequency ( f), and genioglossus (GG) muscle activity but did not alter neuromodulators measured in the effluent mCSF. However, neither unilateral dialysis of a broad spectrum muscarinic receptor antagonist (atropine; 50 mM) nor unilateral or bilateral dialysis of a mixture of excitatory receptor antagonists altered V̇i or GG activity, but all of these did increase HMN serotonin (5-HT) levels. Finally, during night studies, DAMGO and excitatory receptor antagonist decreased ventilatory variables during NREM sleep but not during wakefulness. These findings contrast with previous dialysis studies in the ventral respiratory column (VRC) where unilateral DAMGO or atropine dialysis had no effects on breathing and bilateral DAMGO or unilateral atropine increased V̇i and f and decreased GABA or increased 5-HT, respectively. Thus we conclude that the mechanisms of compensatory neuromodulation are less robust in the HMN than in the VRC under physiological conditions in adult goats, possibly because of site differences in the underlying mechanisms governing neuromodulator release and consequently neuronal activity, and/or responsiveness of receptors to compensatory neuromodulators. NEW & NOTEWORTHY Activation of inhibitory µ-opioid receptors in the hypoglossal motor nucleus decreased ventilation under physiological conditions and did not affect neurochemicals in effluent dialyzed mock cerebral spinal fluid. These findings contrast with studies in the ventral respiratory column where unilateral [d-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) had no effects on ventilation and bilateral DAMGO or unilateral atropine increased ventilation and decreased GABA or increased serotonin, respectively. Our data support the hypothesis that mechanisms that govern local compensatory neuromodulation within the brain stem are site specific under physiological conditions.

scholarly journals Neural Progenitor Cells Undergoing Yap/Tead-Mediated Enhanced Self-Renewal Form Heterotopias More Easily in the Diencephalon than in the Telencephalon

2018 ◽  
Vol 43 (1) ◽  
pp. 180-189 ◽  
Author(s):  
Kanako Saito ◽  
Ryotaro Kawasoe ◽  
Hiroshi Sasaki ◽  
Ayano Kawaguchi ◽  
Takaki Miyata
Keyword(s):  
Progenitor Cells ◽  
Neural Tube ◽  
Neural Progenitor Cells ◽  
Three Dimensional ◽  
Neural Progenitor ◽  
Hippo Signaling ◽  
Apical Surface ◽  
Elevated Expression ◽  
Underlying Mechanisms ◽  
The Brain

Abstract Spatiotemporally ordered production of cells is essential for brain development. Normally, most undifferentiated neural progenitor cells (NPCs) face the apical (ventricular) surface of embryonic brain walls. Pathological detachment of NPCs from the apical surface and their invasion of outer neuronal territories, i.e., formation of NPC heterotopias, can disrupt the overall structure of the brain. Although NPC heterotopias have previously been observed in a variety of experimental contexts, the underlying mechanisms remain largely unknown. Yes-associated protein 1 (Yap1) and the TEA domain (Tead) proteins, which act downstream of Hippo signaling, enhance the stem-like characteristics of NPCs. Elevated expression of Yap1 or Tead in the neural tube (future spinal cord) induces massive NPC heterotopias, but Yap/Tead-induced expansion of NPCs in the developing brain has not been previously reported to produce NPC heterotopias. To determine whether NPC heterotopias occur in a regionally characteristic manner, we introduced the Yap1-S112A or Tead-VP16 into NPCs of the telencephalon and diencephalon, two neighboring but distinct forebrain regions, of embryonic day 10 mice by in utero electroporation, and compared NPC heterotopia formation. Although NPCs in both regions exhibited enhanced stem-like behaviors, heterotopias were larger and more frequent in the diencephalon than in the telencephalon. This result, the first example of Yap/Tead-induced NPC heterotopia in the forebrain, reveals that Yap/Tead-induced NPC heterotopia is not specific to the neural tube, and also suggests that this phenomenon depends on regional factors such as the three-dimensional geometry and assembly of these cells.

Long-term modulation of tyrosine hydroxylase activity and expression by endothelin-1 and -3 in the rat anterior and posterior hypothalamus

2008 ◽  
Vol 294 (3) ◽  
pp. R905-R914 ◽  
Author(s):  
Guadalupe Perfume ◽  
Sabrina L. Nabhen ◽  
Karla Riquelme Barrera ◽  
María G. Otero ◽  
Liliana G. Bianciotti ◽  
...  
Keyword(s):  
Tyrosine Hydroxylase ◽  
Cardiovascular Effects ◽  
Receptor Activation ◽  
Catecholaminergic Neurons ◽  
Endothelin System ◽  
Catecholaminergic Transmission ◽  
Underlying Mechanisms ◽  
G Protein Coupled ◽  
The Brain

Brain catecholamines are involved in the regulation of biological functions, including cardiovascular activity. The hypothalamus presents areas with high density of catecholaminergic neurons and the endothelin system. Two hypothalamic regions intimately related with the cardiovascular control are distinguished: the anterior (AHR) and posterior (PHR) hypothalamus, considered to be sympathoinhibitory and sympathoexcitatory regions, respectively. We previously reported that endothelins (ETs) are involved in the short-term tyrosine hydroxylase (TH) regulation in both the AHR and PHR. TH is crucial for catecholaminergic transmission and is tightly regulated by well-characterized mechanisms. In the present study, we sought to establish the effects and underlying mechanisms of ET-1 and ET-3 on TH long-term modulation. Results showed that in the AHR, ETs decreased TH activity through ETB receptor activation coupled to the nitric oxide, phosphoinositide, and CaMK-II pathways. They also reduced total TH level and TH phosphorylated forms (Ser 19 and 40). Conversely, in the PHR, ETs increased TH activity through a G protein-coupled receptor, likely an atypical ET receptor or the ETC receptor, which stimulated the phosphoinositide and adenylyl cyclase pathways, as well as CaMK-II. ETs also increased total TH level and the Ser 19, 31, and 40 phosphorylated sites of the enzyme. These findings support that ETs are involved in the long-term regulation of TH activity, leading to reduced sympathoinhibition in the AHR and increased sympathoexcitation in the PHR. Present and previous studies may partially explain the cardiovascular effects produced by ETs when applied to the brain.

scholarly journals The Molecular Biology of Brain Metastasis

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Gazanfar Rahmathulla ◽  
Steven A. Toms ◽  
Robert J. Weil
Keyword(s):  
Molecular Biology ◽  
Brain Metastasis ◽  
Targeted Drug Delivery ◽  
Rapid Expansion ◽  
Genetic Mechanisms ◽  
The Central Nervous System ◽  
Targeted Drug ◽  
Underlying Mechanisms ◽  
The Brain ◽  
New Location

Metastasis to the central nervous system (CNS) remains a major cause of morbidity and mortality in patients with systemic cancers. Various crucial interactions between the brain environment and tumor cells take place during the development of the cancer at its new location. The rapid expansion in molecular biology and genetics has advanced our knowledge of the underlying mechanisms involved, from invasion to final colonization of new organ tissues. Understanding the various events occurring at each stage should enable targeted drug delivery and individualized treatments for patients, with better outcomes and fewer side effects. This paper summarizes the principal molecular and genetic mechanisms that underlie the development of brain metastasis (BrM).

scholarly journals P02.08 Visualizing tumor cell - lymphocyte interactions in the brain metastatic cascade using in vivo two photon microscopy

2018 ◽  
Vol 20 (suppl_3) ◽  
pp. iii273-iii273
Author(s):  
M Piechutta ◽  
A S Berghoff ◽  
M A Karreman ◽  
K Gunkel ◽  
W Wick ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Metastatic Cascade ◽  
Two Photon Microscopy ◽  
Two Photon ◽  
The Brain

scholarly journals A Large-scale Comparison of Cortical and Subcortical Structural Segmentation Methods in Alzheimer’s Disease: a Statistical Approach

2020 ◽  
Author(s):  
Jafar Zamani ◽  
Ali Sadr ◽  
Amir-Homayoun Javadi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Automated Segmentation ◽  
Resonance Imaging ◽  
Brain Areas ◽  
Segmentation Methods ◽  
Magnetic Resonance Imaging Mri ◽  
Underlying Mechanisms ◽  
The Brain

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that leads to anatomical atrophy, as evidenced by magnetic resonance imaging (MRI). Automated segmentation methods are developed to help with the segmentation of different brain areas. However, their reliability has yet to be fully investigated. To have a more comprehensive understanding of the distribution of changes in AD, as well as investigating the reliability of different segmentation methods, in this study we compared volumes of cortical and subcortical brain segments, using automated segmentation methods in more than 60 areas between AD and healthy controls (HC).MethodsA total of 44 MRI images (22 AD and 22 HC, 50% females) were taken from the minimal interval resonance imaging in Alzheimer’s disease (MIRIAD) dataset. HIPS, volBrain, CAT and BrainSuite segmentation methods were used for the subfields of hippocampus, and the rest of the brain.ResultsWhile HIPS, volBrain and CAT showed strong conformity with the past literature, BrainSuite misclassified several brain areas. Additionally, the volume of the brain areas that successfully discriminated between AD and HC showed a correlation with mini mental state examination (MMSE) scores. The two methods of volBrain and CAT showed a very strong correlation. These two methods, however, did not correlate with BrainSuite.ConclusionOur results showed that automated segmentation methods HIPS, volBrain and CAT can be used in the classification of AD and HC. This is an indication that such methods can be used to inform researchers and clinicians of underlying mechanisms and progression of AD.

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