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19 pages, 2609 KiB

Open AccessArticle

Cell-Type Dependent Regulation of the Electrogenic Na⁺/HCO₃⁻ Cotransporter 1 (NBCe1) by Hypoxia and Acidosis in Glioblastoma

by Marina Giannaki, Debora E. Ruf, Emilie Pfeifer, Katharina Everaerts, Dieter H. Heiland, Oliver Schnell, Christine R. Rose and Eleni Roussa

Int. J. Mol. Sci. 2022, 23(16), 8975; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23168975 - 11 Aug 2022

Cited by 2 | Viewed by 1714

Abstract

Glioblastoma multiforme (GBM) is the most common and malignant brain tumour. It is characterised by transcriptionally distinct cell populations. In tumour cells, physiological pH gradients between the intracellular and extracellular compartments are reversed, compared to non-cancer cells. Intracellular pH in tumour cells is [...] Read more.

Glioblastoma multiforme (GBM) is the most common and malignant brain tumour. It is characterised by transcriptionally distinct cell populations. In tumour cells, physiological pH gradients between the intracellular and extracellular compartments are reversed, compared to non-cancer cells. Intracellular pH in tumour cells is alkaline, whereas extracellular pH is acidic. Consequently, the function and/or expression of pH regulating transporters might be altered. Here, we investigated protein expression and regulation of the electrogenic sodium/bicarbonate cotransporter 1 (NBCe1) in mesenchymal (MES)-like hypoxia-dependent and -independent cells, as well as in astrocyte-like glioblastoma cells following chemical hypoxia, acidosis and elucidated putative underlying molecular pathways. Immunoblotting, immunocytochemistry, and intracellular pH recording with the H⁺-sensitive dye 2′,7′-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein were applied. The results show NBCe1 protein abundance and active NBCe1 transport. Hypoxia upregulated NBCe1 protein and activity in MES-like hypoxia-dependent GBM cells. This effect was positively correlated with HIF-1α protein levels, was mediated by TGF-β signalling, and was prevented by extracellular acidosis. In MES-like hypoxia-independent GBM cells, acidosis (but not hypoxia) regulated NBCe1 activity in an HIF-1α-independent manner. These results demonstrate a cell-specific adaptation of NBCe1 expression and activity to the microenvironment challenge of hypoxia and acidosis that depends on their transcriptional signature in GBM. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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16 pages, 3465 KiB

Open AccessArticle

Recognition of a Novel Gene Signature for Human Glioblastoma

by Chih-Hao Lu, Sung-Tai Wei, Jia-Jun Liu, Yu-Jen Chang, Yu-Feng Lin, Chin-Sheng Yu and Sunny Li-Yun Chang

Int. J. Mol. Sci. 2022, 23(8), 4157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084157 - 09 Apr 2022

Cited by 9 | Viewed by 2890

Abstract

Glioblastoma (GBM) is one of the most common malignant and incurable brain tumors. The identification of a gene signature for GBM may be helpful for its diagnosis, treatment, prediction of prognosis and even the development of treatments. In this study, we used the [...] Read more.

Glioblastoma (GBM) is one of the most common malignant and incurable brain tumors. The identification of a gene signature for GBM may be helpful for its diagnosis, treatment, prediction of prognosis and even the development of treatments. In this study, we used the GSE108474 database to perform GSEA and machine learning analysis, and identified a 33-gene signature of GBM by examining astrocytoma or non-GBM glioma differential gene expression. The 33 identified signature genes included the overexpressed genes COL6A2, ABCC3, COL8A1, FAM20A, ADM, CTHRC1, PDPN, IBSP, MIR210HG, GPX8, MYL9 and PDLIM4, as well as the underexpressed genes CHST9, CSDC2, ENHO, FERMT1, IGFN1, LINC00836, MGAT4C, SHANK2 and VIPR2. Protein functional analysis by CELLO2GO implied that these signature genes might be involved in regulating various aspects of biological function, including anatomical structure development, cell proliferation and adhesion, signaling transduction and many of the genes were annotated in response to stress. Of these 33 signature genes, 23 have previously been reported to be functionally correlated with GBM; the roles of the remaining 10 genes in glioma development remain unknown. Our results were the first to reveal that GBM exhibited the overexpressed GPX8 gene and underexpressed signature genes including CHST9, CSDC2, ENHO, FERMT1, IGFN1, LINC00836, MGAT4C and SHANK2, which might play crucial roles in the tumorigenesis of different gliomas. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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17 pages, 6262 KiB

Open AccessArticle

Acute and Delayed Effects of Mechanical Injury on Calcium Homeostasis and Mitochondrial Potential of Primary Neuroglial Cell Culture: Potential Causal Contributions to Post-Traumatic Syndrome

by Zanda Bakaeva, Mikhail Goncharov, Irina Krasilnikova, Arina Zgodova, Daniil Frolov, Ekaterina Grebenik, Peter Timashev, Vsevolod Pinelis and Alexander Surin

Int. J. Mol. Sci. 2022, 23(7), 3858; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073858 - 31 Mar 2022

Cited by 5 | Viewed by 2117

Abstract

In vitro models of traumatic brain injury (TBI) help to elucidate the pathological mechanisms responsible for cell dysfunction and death. To simulate in vitro the mechanical brain trauma, primary neuroglial cultures were scratched during different periods of network formation. Fluorescence microscopy was used [...] Read more.

In vitro models of traumatic brain injury (TBI) help to elucidate the pathological mechanisms responsible for cell dysfunction and death. To simulate in vitro the mechanical brain trauma, primary neuroglial cultures were scratched during different periods of network formation. Fluorescence microscopy was used to measure changes in intracellular free Ca²⁺ concentration ([Ca²⁺]_i) and mitochondrial potential (ΔΨm) a few minutes later and on days 3 and 7 after scratching. An increase in [Ca²⁺]_i and a decrease in ΔΨm were observed ~10 s after the injury in cells located no further than 150–200 µm from the scratch border. Ca²⁺ entry into cells during mechanical damage of the primary neuroglial culture occurred predominantly through the NMDA-type glutamate ionotropic channels. MK801, an inhibitor of this type of glutamate receptor, prevented an acute increase in [Ca²⁺]_i in 99% of neurons. Pathological changes in calcium homeostasis persisted in the primary neuroglial culture for one week after injury. Active cell migration in the scratch area occurred on day 11 after neurotrauma and was accompanied by a decrease in the ratio of live to dead cells in the areas adjacent to the injury. Immunohistochemical staining of glial fibrillary acidic protein and β-III tubulin showed that neuronal cells migrated to the injured area earlier than glial cells, but their repair potential was insufficient for survival. Mitochondrial Ca²⁺ overload and a drop in ΔΨm may cause delayed neuronal death and thus play a key role in the development of the post-traumatic syndrome. Preventing prolonged ΔΨm depolarization may be a promising therapeutic approach to improve neuronal survival after traumatic brain injury. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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14 pages, 4456 KiB

Open AccessArticle

Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells

by Wioleta Justyna Omeljaniuk, Rafał Krętowski, Wioletta Ratajczak-Wrona, Ewa Jabłońska and Marzanna Cechowska-Pasko

Int. J. Mol. Sci. 2021, 22(21), 11511; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111511 - 26 Oct 2021

Cited by 19 | Viewed by 2483

Abstract

Deregulated PI3K/AKT/mTOR signalling commonly exists in glioblastoma, making this axis an attractive target for therapeutic manipulation. Given that activation of PI3K/AKT/mTOR promotes tumour growth, metastasis, and resistance to anticancer therapies, mTOR inhibitors show promise in the treatment of cancer. The aim of this [...] Read more.

Deregulated PI3K/AKT/mTOR signalling commonly exists in glioblastoma, making this axis an attractive target for therapeutic manipulation. Given that activation of PI3K/AKT/mTOR promotes tumour growth, metastasis, and resistance to anticancer therapies, mTOR inhibitors show promise in the treatment of cancer. The aim of this study was to investigate the underlying mechanism of novel dual PI3K/mTOR inhibitor, Apitolisib (GDC-0980), in A-172 and U-118-MG GBM tumour cell line suppression. It has been demonstrated that GDC-0980 induces time- and dose-dependent cytotoxicity and apoptosis in investigated glioma cell lines. In our study, the strongest induction of apoptosis was exhibited in the A-172 line after 48 h of incubation with 20 µM GDC-0980, where we observed 46.47% of apoptotic cells. In conclusion, we first discovered that dual PI3K/mTOR blockade by GDC-0980 markedly suppressed survival of human GBM cells and induced apoptosis, independent of the ER stress-mediated DR5 activation. We suggest that GDC-0980, by exerting an inhibitory effect on PERK expression, may thus block its inhibitory effect on protein synthesis, leading to intensification of translation, and this may result in an increase in apoptosis. On the other hand, CHOP stimulates protein synthesis and increases apoptosis. These findings suggest that GDC-0980 may be a candidate for further evaluation as a chemotherapeutic agent for anti-GBM therapy. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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15 pages, 49943 KiB

Open AccessArticle

Oligodendrocyte-Specific Deletion of FGFR1 Reduces Cerebellar Inflammation and Neurodegeneration in MOG_35-55-Induced EAE

by Ranjithkumar Rajendran, Vinothkumar Rajendran, Mario Giraldo-Velasquez, Fevronia-Foivi Megalofonou, Fynn Gurski, Christine Stadelmann, Srikanth Karnati and Martin Berghoff

Int. J. Mol. Sci. 2021, 22(17), 9495; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179495 - 31 Aug 2021

Cited by 6 | Viewed by 3456

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of FGFRs results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of FGFR1 in oligodendrocytes in the cerebellum. Conditional deletion of FGFR1 in oligodendrocytes (Fgfr1^ind−/−) was achieved by tamoxifen application, EAE was induced using the MOG_35-55 peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., Fgfr1^ind−/− mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in Fgfr1^ind−/−mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in Fgfr1^ind−/− mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in Fgfr1^ind−/− mice. These data suggest that cell-specific deletion of FGFR1 in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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Review

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16 pages, 817 KiB

Open AccessReview

FGFR3-TACCs3 Fusions and Their Clinical Relevance in Human Glioblastoma

by Hanna Gött and Eberhard Uhl

Int. J. Mol. Sci. 2022, 23(15), 8675; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158675 - 04 Aug 2022

Cited by 7 | Viewed by 4402

Abstract

Oncogenic fusion genes have emerged as successful targets in several malignancies, such as chronic myeloid leukemia and lung cancer. Fusion of the fibroblast growth receptor 3 and the transforming acidic coiled coil containing protein—FGFR3-TACC3 fusion—is prevalent in 3–4% of human glioblastoma. The fusion [...] Read more.

Oncogenic fusion genes have emerged as successful targets in several malignancies, such as chronic myeloid leukemia and lung cancer. Fusion of the fibroblast growth receptor 3 and the transforming acidic coiled coil containing protein—FGFR3-TACC3 fusion—is prevalent in 3–4% of human glioblastoma. The fusion protein leads to the constitutively activated kinase signaling of FGFR3 and thereby promotes cell proliferation and tumor progression. The subgroup of FGFR3-TACC3 fusion-positive glioblastomas presents with recurrent clinical and histomolecular characteristics, defining a distinctive subtype of IDH-wildtype glioblastoma. This review aims to provide an overview of the available literature on FGFR3-TACC3 fusions in glioblastoma and possible implications for actual clinical practice. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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19 pages, 1047 KiB

Open AccessReview

Neurotrophin Signaling Impairment by Viral Infections in the Central Nervous System

by Karen Bohmwald, Catalina A. Andrade, Valentina P. Mora, José T. Muñoz, Robinson Ramírez, María F. Rojas and Alexis M. Kalergis

Int. J. Mol. Sci. 2022, 23(10), 5817; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105817 - 22 May 2022

Cited by 9 | Viewed by 3054

Abstract

Neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), NT-4, and NT-5, are proteins involved in several important functions of the central nervous system. The activation of the signaling pathways of these neurotrophins, or even by their [...] Read more.

Neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin 3 (NT-3), NT-4, and NT-5, are proteins involved in several important functions of the central nervous system. The activation of the signaling pathways of these neurotrophins, or even by their immature form, pro-neurotrophins, starts with their recognition by cellular receptors, such as tropomyosin receptor kinase (Trk) and 75 kD NT receptors (p75NTR). The Trk receptor is considered to have a high affinity for attachment to specific neurotrophins, while the p75NTR receptor has less affinity for attachment with neurotrophins. The correct functioning of these signaling pathways contributes to proper brain development, neuronal survival, and synaptic plasticity. Unbalanced levels of neurotrophins and pro-neurotrophins have been associated with neurological disorders, illustrating the importance of these molecules in the central nervous system. Furthermore, reports have indicated that viruses can alter the normal levels of neurotrophins by interfering with their signaling pathways. This work discusses the importance of neurotrophins in the central nervous system, their signaling pathways, and how viruses can affect them. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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16 pages, 792 KiB

Open AccessReview

Role of Intracellular Amyloid β as Pathway Modulator, Biomarker, and Therapy Target

by Lucia Gallego Villarejo, Lisa Bachmann, David Marks, Maite Brachthäuser, Alexander Geidies and Thorsten Müller

Int. J. Mol. Sci. 2022, 23(9), 4656; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094656 - 22 Apr 2022

Cited by 15 | Viewed by 2918

Abstract

The β- and γ-secretase-driven cleavage of the amyloid precursor protein (APP) gives rise to the amyloid β peptide, which is believed to be the main driver of neurodegeneration in Alzheimer’s disease (AD). As it is prominently detectable in extracellular plaques in post-mortem AD [...] Read more.

The β- and γ-secretase-driven cleavage of the amyloid precursor protein (APP) gives rise to the amyloid β peptide, which is believed to be the main driver of neurodegeneration in Alzheimer’s disease (AD). As it is prominently detectable in extracellular plaques in post-mortem AD brain samples, research in recent decades focused on the pathological role of extracellular amyloid β aggregation, widely neglecting the potential meaning of very early generation of amyloid β inside the cell. In the last few years, the importance of intracellular amyloid β (iAβ) as a strong player in neurodegeneration has been indicated by a rising number of studies. In this review, iAβ is highlighted as a crucial APP cleavage fragment, able to manipulate intracellular pathways and foster neurodegeneration. We demonstrate its relevance as a pathological marker and shed light on initial studies aiming to modulate iAβ through pharmacological treatment, which has been shown to have beneficial effects on cognitive properties in animal models. Finally, we display the relevance of viral infections on iAβ generation and point out future directions urgently needed to manifest the potential relevance of iAβ in Alzheimer’s disease. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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14 pages, 1378 KiB

Open AccessReview

SARS-CoV-2 Morbidity in the CNS and the Aged Brain Specific Vulnerability

by Tiziana Casoli

Int. J. Mol. Sci. 2022, 23(7), 3782; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073782 - 29 Mar 2022

Cited by 2 | Viewed by 2575

Abstract

The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be the cause of a fatal disease known as coronavirus disease 2019 (COVID-19) affecting the lungs and other organs. Particular attention has been given to the effects of the infection on the [...] Read more.

The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be the cause of a fatal disease known as coronavirus disease 2019 (COVID-19) affecting the lungs and other organs. Particular attention has been given to the effects of the infection on the brain due to recurring neurological symptoms associated with COVID-19, such as ischemic or hemorrhagic stroke, encephalitis and myelitis, which are far more severe in the elderly compared to younger patients. The specific vulnerability of the aged brain could derive from the impaired immune defenses, from any of the altered homeostatic mechanisms that contribute to the aging phenotype, and from particular changes in the aged brain involving neurons and glia. While neuronal modifications could contribute indirectly to the damage induced by SARS-CoV-2, glia alterations could play a more direct role, as they are involved in the immune response to viral infections. In aged patients, changes regarding glia include the accumulation of dystrophic forms, reduction of waste removal, activation of microglia and astrocytes, and immunosenescence. It is plausible to hypothesize that SARS-CoV-2 infection in the elderly may determine severe brain damage because of the frail phenotype concerning glial cells. Full article

(This article belongs to the Special Issue Molecular Signaling Pathways in Brain Pathology)

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