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1.
Front Cell Neurosci ; 17: 1211446, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37545879

RESUMO

Background: Toxoplasmosis affects one third of the world population and has the protozoan Toxoplasma gondii as etiological agent. Congenital toxoplasmosis (CT) can cause severe damage to the fetus, including miscarriages, intracranial calcification, hydrocephalus and retinochoroiditis. Severity of CT depends on the gestational period in which infection occurs, and alterations at the cellular level during retinal development have been reported. In this study, we proposed a mouse CT model to investigate the impact of infection on retinal development. Methods: Pregnant females of pigmented C57BL/6 strain mice were infected intragastrically with two T. gondii cysts (ME49 strain) at embryonic day 10 (E10), and the offspring were analyzed at E18. Results: Infected embryos had significantly smaller body sizes and weights than the PBS-treated controls, indicating that embryonic development was affected. In the retina, a significant increase in the number of Ki-67-positive cells (marker of proliferating cells) was found in the apical region of the NBL of infected mice compared to the control. Supporting this, cell cycle proteins Cyclin D3, Cdk6 and pChK2 were significantly altered in infected retinas. Interestingly, the immunohistochemical analysis showed a significant increase in the population of ß-III-tubulin-positive cells, one of the earliest markers of neuronal differentiation. Conclusions: Our data suggests that CT affects cell cycle progression in retinal progenitor cells, possibly inducing the arrest of these cells at G2/M phase. Such alterations could influence the differentiation, anticipating/increasing neuronal maturation, and therefore leading to abnormal retinal formation. Our model mimics important events observed in ocular CT.

2.
Viruses ; 15(3)2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36992454

RESUMO

Neurological effects of COVID-19 and long-COVID-19, as well as neuroinvasion by SARS-CoV-2, still pose several questions and are of both clinical and scientific relevance. We described the cellular and molecular effects of the human brain microvascular endothelial cells (HBMECs) in vitro exposure by SARS-CoV-2 to understand the underlying mechanisms of viral transmigration through the blood-brain barrier. Despite the low to non-productive viral replication, SARS-CoV-2-exposed cultures displayed increased immunoreactivity for cleaved caspase-3, an indicator of apoptotic cell death, tight junction protein expression, and immunolocalization. Transcriptomic profiling of SARS-CoV-2-challenged cultures revealed endothelial activation via NF-κB non-canonical pathway, including RELB overexpression and mitochondrial dysfunction. Additionally, SARS-CoV-2 led to altered secretion of key angiogenic factors and to significant changes in mitochondrial dynamics, with increased mitofusin-2 expression and increased mitochondrial networks. Endothelial activation and remodeling can further contribute to neuroinflammatory processes and lead to further BBB permeability in COVID-19.


Assuntos
COVID-19 , NF-kappa B , Humanos , NF-kappa B/metabolismo , SARS-CoV-2/metabolismo , Células Endoteliais/metabolismo , Síndrome de COVID-19 Pós-Aguda , COVID-19/metabolismo , Encéfalo , Barreira Hematoencefálica , Mitocôndrias/metabolismo
3.
J Mol Med (Berl) ; 100(10): 1405-1425, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36056255

RESUMO

Cellular prion protein (PrPC) is a highly conserved glycoprotein, present both anchored in the cell membrane and soluble in the extracellular medium. It has a diversity of ligands and is variably expressed in numerous tissues and cell subtypes, most notably in the central nervous system (CNS). Its importance has been brought to light over the years both under physiological conditions, such as embryogenesis and immune system homeostasis, and in pathologies, such as cancer and neurodegenerative diseases. During development, PrPC plays an important role in CNS, participating in axonal growth and guidance and differentiation of glial cells, but also in other organs such as the heart, lung, and digestive system. In diseases, PrPC has been related to several types of tumors, modulating cancer stem cells, enhancing malignant properties, and inducing drug resistance. Also, in non-neoplastic diseases, such as Alzheimer's and Parkinson's diseases, PrPC seems to alter the dynamics of neurotoxic aggregate formation and, consequently, the progression of the disease. In this review, we explore in detail the multiple functions of this protein, which proved to be relevant for understanding the dynamics of organism homeostasis, as well as a promising target in the treatment of both neoplastic and degenerative diseases.


Assuntos
Neoplasias , Doenças Neurodegenerativas , Proteínas PrPC , Sistema Nervoso Central/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Proteínas PrPC/genética , Proteínas PrPC/metabolismo
4.
bioRxiv ; 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35734080

RESUMO

Neurological effects of COVID-19 and long-COVID-19 as well as neuroinvasion by SARS-CoV-2 still pose several questions and are of both clinical and scientific relevance. We described the cellular and molecular effects of the human brain microvascular endothelial cells (HBMECs) in vitro infection by SARS-CoV-2 to understand the underlying mechanisms of viral transmigration through the Blood-Brain Barrier. Despite the low to non-productive viral replication, SARS-CoV-2-infected cultures displayed increased apoptotic cell death and tight junction protein expression and immunolocalization. Transcriptomic profiling of infected cultures revealed endothelial activation via NF-κB non-canonical pathway, including RELB overexpression, and mitochondrial dysfunction. Additionally, SARS-CoV-2 led to altered secretion of key angiogenic factors and to significant changes in mitochondrial dynamics, with increased mitofusin-2 expression and increased mitochondrial networks. Endothelial activation and remodeling can further contribute to neuroinflammatory processes and lead to further BBB permeability in COVID-19.

5.
Cytokine Growth Factor Rev ; 57: 73-84, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32561134

RESUMO

Stress inducible protein 1 (STI1) is a co-chaperone acting with Hsp70 and Hsp90 for the correct client proteins' folding and therefore for the maintenance of cellular homeostasis. Besides being expressed in the cytosol, STI1 can also be found both in the cell membrane and the extracellular medium playing several relevant roles in the central nervous system (CNS) and tumor microenvironment. During CNS development, in association with cellular prion protein (PrPc), STI1 regulates crucial events such as neuroprotection, neuritogenesis, astrocyte differentiation and survival. In cancer, STI1 is involved with tumor growth and invasion, is undoubtedly a pro-tumor factor, being considered as a biomarker and possibly therapeutic target for several malignancies. In this review, we discuss current knowledge and new findings on STI1 function as well as its role in tissue homeostasis, CNS and tumor progression.


Assuntos
Chaperonas Moleculares , Proteínas de Choque Térmico , Humanos , Microambiente Tumoral
6.
Anticancer Res ; 40(5): 2725-2737, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366418

RESUMO

BACKGROUND/AIM: Glioblastoma (GB) is the most aggressive type of tumor in the central nervous system and is characterized by resistance to therapy and abundant vasculature. Tumor vessels contribute to the growth of GB, and the tumor microenvironment is thought to influence tumor vessels. We evaluated the molecular communication between human GB cells and human brain microvascular endothelial cells (HBMEC) in vitro. MATERIALS AND METHODS: We investigated whether GB-conditioned media (GB-CM) influenced HBMEC proliferation and migration, as well as the levels of MMP-9, CXCL12, CXCR4, CXCR7, VEGFs, VEGFR-2, and WNT5a in HBMEC. RESULTS: Although HBMEC proliferation was not modified, increased HBMEC migration was detected after GB-CM treatment. Furthermore, treatment of HBMEC with GB-CM resulted in increased levels of MMP-9 and CXCR4. The levels of WNT5a, VEGFs and VEGFR-2 were not affected. CONCLUSION: GB-secreted factors lead to increased endothelial cell migration and to increased levels of MMP-9 and CXCR4.


Assuntos
Neoplasias Encefálicas/patologia , Encéfalo/patologia , Movimento Celular , Células Endoteliais/patologia , Glioblastoma/patologia , Metaloproteinase 9 da Matriz/metabolismo , Receptores CXCR4/metabolismo , Neoplasias Encefálicas/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo
7.
Trends Cancer ; 5(1): 46-65, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30616755

RESUMO

Glioblastoma (GBM) is the most common and fatal primary malignant brain tumor. Despite advances in the understanding of the biology of gliomas, little has changed in the treatment of these tumors in the past decade. Phase III clinical trials showed no benefit for the use of bevacizumab in newly diagnosed patients, leading to a renewed search for new antiangiogenic drugs, as well as immunotherapeutic approaches, including checkpoint inhibitors, chimeric antigen receptor T cells, and intracerebral CpG-oligodeoxynucleotides. The emerging role of infiltrating microglia and macrophages, and of metabolic alterations, is also being taken into account in preclinical research and drug development. In this review, we discuss progress in the search for new therapeutic strategies, particularly approaches focusing on the tumor microenvironment.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Terapia de Alvo Molecular , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Metabolismo Energético/efeitos dos fármacos , Terapia Genética , Glioblastoma/etiologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Imunoterapia Adotiva/métodos , Terapia de Alvo Molecular/métodos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
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