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1.
Res Sq ; 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38659765

RESUMO

Disruptions in pericyte and endothelial cell expression can compromise the integrity of the blood-brain barrier (BBB), leading to neurovascular dysfunction and the development of neurological disorders. However, the study of microvessel RNAs has been limited to tissue homogenates, with spatial visualization only available for protein targets. We introduce an innovative microvessel isolation technique that is RNA-friendly for the purpose of coupling with RNAscope analysis. RNA-friendly microvessel isolation combined with RNAscope analysis enables the visualization of cell-specific RNA within the spatial and histological context of the BBB. Using this approach, we have gained valuable insights into the structural and functional differences associated with the microvessels of 5XFAD mice, a mouse model of Alzheimer's disease (AD). RNAscope analysis revealed a decrease in pericytes from microvessels isolated from 5XFAD mice in comparison to wild-type mice. Additionally, the microvessels of 5XFAD mice exhibited an increase in TYROBP mRNA expression. These findings significantly advance our understanding of neurovascular interactions and hold great promise for guiding the development of targeted therapeutic interventions. This innovative approach enables visualization of cell RNA while preserving the spatial and histological context of the BBB, shedding light on the mechanisms underlying neurovascular unit communication.

2.
J Biol Chem ; 300(1): 105526, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38043797

RESUMO

Despite antiretroviral therapy (ART), chronic forms of HIV-associated neurocognitive disorders (HAND) affect an estimated 50% of individuals living with HIV, greatly impacting their quality of life. The prevailing theory of HAND progression posits that chronic inflammation arising from the activation of latent viral reservoirs leads to progressive damage in the central nervous system (CNS). Recent evidence indicates that blood-brain barrier (BBB) pericytes are capable of active HIV-1 infection; however, their latent infection has not been defined. Given their location and function, BBB pericytes are poised to be a key viral reservoir in the development of HAND. We present the first transcriptional analysis of uninfected, active, and latent human BBB pericytes, revealing distinct transcriptional phenotypes. In addition, we demonstrate that latent infection of BBB pericytes relies on AKT signaling for reservoir survival. These findings provide insight into the state of reservoir maintenance in the CNS during HIV-1 infection and provide novel targets for reservoir clearance.


Assuntos
Barreira Hematoencefálica , Reservatórios de Doenças , Infecções por HIV , HIV-1 , Infecção Latente , Pericitos , Humanos , Barreira Hematoencefálica/virologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Infecções por HIV/virologia , Infecção Latente/virologia , Pericitos/virologia , Proteínas Proto-Oncogênicas c-akt/genética , Qualidade de Vida , Latência Viral , Reservatórios de Doenças/virologia
3.
Am J Physiol Cell Physiol ; 326(2): C487-C504, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38145295

RESUMO

Blood-brain barrier (BBB) breakdown is one of the pathophysiological characteristics of ischemic stroke, which may contribute to the progression of brain tissue damage and subsequent neurological impairment. Human immunodeficiency virus (HIV)-infected individuals are at greater risk for ischemic stroke due to diminished immune function and HIV-associated vasculopathy. Studies have shown that astrocytes are involved in maintaining BBB integrity and facilitating HIV-1 infection in the brain. The present study investigated whether targeting astrocyte-endothelial cell signaling with cenicriviroc (CVC), a dual chemokine receptor (CCR)2 and CCR5 antagonist, may protect against dysregulation of cross talk between these cells after oxygen-glucose deprivation/reoxygenation (OGD/R) combined with HIV-1 infection. Permeability assay with 10 kDa fluorescein isothiocyanate (FITC)-dextran demonstrated that CVC alleviated endothelial barrier disruption in noncontact coculture of human brain microvascular endothelial cells (HBMECs) with HIV-1-infected human astrocytes, and reversed downregulation of tight junction protein claudin-5 induced by OGD/R- and HIV-1. Moreover, CVC attenuated OGD/R- and HIV-1-triggered upregulation of the NOD-like receptor protein-3 (NLRP3) inflammasome and IL-1ß secretion. Treatment with CVC also suppressed astrocyte pyroptosis by attenuating cleaved caspase-1 levels and the formation of cleaved N-terminal GSDMD (N-GSDMD). Secretome profiling revealed that CVC ameliorated secretion levels of chemokine CC chemokine ligand 17 (CCL17), adhesion molecule intercellular adhesion molecule-1 (ICAM-1), and T cell activation modulator T cell immunoglobulin and mucin domain 3 (TIM-3) by astrocytes synergistically induced by OGD/R and HIV-1. Overall, these results suggest that CVC contributes to restoring astrocyte-endothelial cross interactions in an astrocyte-dependent manner via protection against NLRP3 activation and pyroptosis.NEW & NOTEWORTHY The present study reveals the role of astrocytic NOD-like receptor protein-3 (NLRP3) inflammasome in dysfunctional astrocyte-endothelial cross interactions triggered in response to oxygen/glucose deprivation injury associated with human immunodeficiency virus type 1 (HIV-1) infection. Our results suggest that blocking NLRP3 inflammasome activation and pyroptosis-mediated inflammation with cenicriviroc (CVC) may constitute a potentially effective therapeutic strategy for blood-brain barrier (BBB) protection during HIV-1-associated ischemic stroke.


Assuntos
Infecções por HIV , HIV-1 , Imidazóis , AVC Isquêmico , Sulfóxidos , Humanos , Astrócitos/metabolismo , Inflamassomos/metabolismo , Inflamassomos/farmacologia , HIV-1/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Células Endoteliais/metabolismo , Piroptose , Proteínas NLR/metabolismo , Oxigênio/metabolismo , Isquemia/metabolismo , AVC Isquêmico/metabolismo , Glucose/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo
4.
Fluids Barriers CNS ; 20(1): 73, 2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37840143

RESUMO

Compromised structure and function of the blood-brain barrier (BBB) is one of the pathological hallmarks of brain infection by HIV-1. BBB damage during HIV-1 infection has been associated with modified expression of tight junction (TJ) proteins, including occludin. Recent evidence indicated occludin as a redox-sensitive, multifunctional protein that can act as both an NADH oxidase and influence cellular metabolism through AMPK kinase. One of the newly identified functions of occludin is its involvement in regulating HIV-1 infection. Studies suggest that occludin expression levels and the rate of HIV-1 infection share a reverse, bidirectional relationship; however, the mechanisms of this relationship are unclear. In this review, we describe the pathways involved in the regulation of HIV-1 infection by occludin. We propose that occludin may serve as a potential therapeutic target to control HIV-1 infection and to improve the lives of people living with HIV-1.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Ocludina/metabolismo , HIV-1/metabolismo , Encéfalo/metabolismo , Barreira Hematoencefálica/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo
5.
Trends Neurosci ; 46(8): 682-693, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37330380

RESUMO

HIV-associated comorbidities, such as ischemic stroke, are prevalent in people with HIV (PWH). Several studies both in animal models and humans have revealed an association between activation of the inflammasome in HIV-1 infection and stroke. The gut microbiota is an important component in controlling neuroinflammation in the CNS. It has also been proposed to be involved in the pathobiology of HIV-1 infection, and has been associated with an increase in activation of the inflammasome. In this review, we provide an overview of the microbiota-gut-inflammasome-brain axis, focusing on the NLRP3 inflammasome and dysregulation of the microbiome as risk factors that may contribute to the outcome of ischemic stroke and recovery in PWH. We also focus on the potential of targeting the NLRP3 inflammasome as a novel therapeutic approach for PWH who are at risk of developing cerebrovascular diseases.


Assuntos
Infecções por HIV , HIV-1 , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Humanos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , AVC Isquêmico/complicações , Disbiose/complicações , Acidente Vascular Cerebral/complicações , Infecções por HIV/complicações
6.
J Hazard Mater ; 454: 131499, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37126901

RESUMO

Polychlorinated biphenyls (PCBs) are lipophilic and persistent environmental toxicants, which pose health threats to the exposed population. Among several organs and cell types, vascular tissue and endothelial cells are especially prone to PCB-induced toxicity. Exposure to PCBs can exert detrimental impacts on biological pathways, expression of transcription factors, and tight junction proteins that are integral to the functionality of endothelial cells. Because biological and cellular processes are tightly regulated by circadian rhythms, and disruption of the circadian system may cause several diseases, we evaluated if exposure to PCBs can alter the expression of the major endothelial circadian regulators. In addition, we studied if dysregulation of circadian rhythms by silencing the brain and muscle ARNT-like 1 (Bmal1) gene can contribute to alterations of brain endothelial cells in response to PCB treatment. We demonstrated that diminished expression of Bmal1 enhances PCB-induced dysregulation of tight junction complexes, such as the expression of occludin, JAM-2, ZO-1, and ZO-2 especially at pathologically relevant longer PCB exposure times. Overall, the obtained results imply that dysregulation of the circadian clock is involved in endothelial toxicity of PCBs. The findings provide new insights for toxicological studies focused on the interactions between environmental pollutants and regulation of circadian rhythms.


Assuntos
Relógios Circadianos , Poluentes Ambientais , Bifenilos Policlorados , Bifenilos Policlorados/toxicidade , Células Endoteliais , Relógios Circadianos/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Poluentes Ambientais/toxicidade
7.
Mol Neurobiol ; 60(9): 4966-4982, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37209263

RESUMO

HIV-1-associated blood brain barrier (BBB) alterations and neurocognitive disorders are frequent clinical manifestations in HIV-1 infected patients. The BBB is formed by cells of the neurovascular unit (NVU) and sealed together by tight junction proteins, such as occludin (ocln). Pericytes are a key cell type of NVU that can harbor HIV-1 infection via a mechanism that is regulated, at least in part, by ocln. After viral infection, the immune system starts the production of interferons, which induce the expression of the 2'-5'-oligoadenylate synthetase (OAS) family of interferon stimulated genes and activate the endoribonuclease RNaseL that provides antiviral protection by viral RNA degradation. The current study evaluated the involvement of the OAS genes in HIV-1 infection of cells of NVU and the role of ocln in controlling OAS antiviral signaling pathway. We identified that ocln modulates the expression levels of the OAS1, OAS2, OAS3, and OASL genes and proteins and, in turn, that the members of the OAS family can influence HIV replication in human brain pericytes. Mechanistically, this effect was regulated via the STAT signaling. HIV-1 infection of pericytes significantly upregulated expression of all OAS genes at the mRNA level but selectively OAS1, OAS2, and OAS3 at the protein level. Interestingly no changes were found in RNaseL after HIV-1 infection. Overall, these results contribute to a better understanding of the molecular mechanisms implicated in the regulation of HIV-1 infection in human brain pericytes and suggest a novel role for ocln in controlling of this process.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Interferons , Ocludina/genética , HIV-1/metabolismo , 2',5'-Oligoadenilato Sintetase/genética , Infecções por HIV/genética , Antivirais
8.
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
9.
Res Sq ; 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36778388

RESUMO

HIV-1-associated blood brain barrier (BBB) alterations and neurocognitive disorders are frequent clinical manifestations in HIV-1 infected patients. The BBB is formed by cells of the neurovascular unit (NVU) and sealed together by tight junction (TJ) proteins, such as occludin (ocln). Pericytes are a key cell type of NVU that can harbor HIV-1 infection via a mechanism that is regulated, at least in part, by ocln. After viral infection, the immune system starts the production of interferons, which induce the expression of the 2'-5'-oligoadenylate synthetase (OAS) family of interferon stimulated genes and activate the endoribonuclease RNaseL that provides antiviral protection by viral RNA degradation. The current study evaluated the involvement of the OAS genes in HIV-1 infection of cells of NVU and the role of ocln in controlling OAS antiviral signaling pathway. We identified that ocln modulates the expression levels of the OAS1, OAS2, OAS3, and OASL genes and proteins and, in turn, that the members of the OAS family can influence HIV replication in human brain pericytes. Mechanistically, this effect was regulated via the STAT signaling. HIV-1 infection of pericytes significantly upregulated expression of all OAS genes at the mRNA level but selectively OAS1, OAS2 and OAS3 at the protein level. Interestingly no changes were found in RNaseL after HIV-1 infection. Overall, these results contribute to a better understanding of the molecular mechanisms implicated in the regulation of HIV-1 infection in human brain pericytes and suggest a novel role for ocln in controlling of this process.

10.
Retrovirology ; 19(1): 27, 2022 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-36476484

RESUMO

While HIV-1 is primarily an infection of CD4 + T cells, there is an emerging interest towards understanding how infection of other cell types can contribute to HIV-associated comorbidities. For HIV-1 to cross from the blood stream into tissues, the virus must come in direct contact with the vascular endothelium, including pericytes that envelope vascular endothelial cells. Pericytes are multifunctional cells that have been recognized for their essential role in angiogenesis, vessel maintenance, and blood flow rate. Most importantly, recent evidence has shown that pericytes can be a target of HIV-1 infection and support an active stage of the viral life cycle, with latency also suggested by in vitro data. Pericyte infection by HIV-1 has been confirmed in the postmortem human brains and in lungs from SIV-infected macaques. Moreover, pericyte dysfunction has been implicated in a variety of pathologies ranging from ischemic stroke to diabetes, which are common comorbidities among people with HIV-1. In this review, we discuss the role of pericytes during HIV-1 infection and their contribution to the progression of HIV-associated comorbidities.


Assuntos
Infecções por HIV , HIV-1 , Humanos , Células Endoteliais
11.
J Vis Exp ; (188)2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-36282703

RESUMO

Ischemic stroke is a major cause of death and disability worldwide with limited therapeutic options. The neuropathology of ischemic stroke is characterized by an interruption in blood supply to the brain leading to cell death and cognitive dysfunction. During and after ischemic stroke, blood-brain barrier (BBB) dysfunction facilitates injury progression and contributes to poor patient recovery. Current BBB models primarily include endothelial monocultures and double co-cultures with either astrocytes or pericytes. Such models lack the ability to fully imitate a dynamic brain microenvironment, which is essential for cell-to-cell communication. Additionally, commonly used BBB models often contain immortalized human endothelial cells or animal-derived (rodent, porcine, or bovine) cell cultures that pose translational limitations. This paper describes a novel well-insert-based BBB model containing only primary human cells (brain microvascular endothelial cells, astrocytes, and brain vascular pericytes) enabling the investigation of ischemic brain injury in vitro. The effects of oxygen-glucose deprivation (OGD) on barrier integrity were assessed by passive permeability, transendothelial electrical resistance (TEER) measurements,and direct visualization of hypoxic cells. The presented protocol offers a distinct advantage inmimicking the intercellular environment of the BBB in vivo, serving as a more realistic in vitro BBB model for developing new therapeutic strategies in the setting of ischemic brain injury.


Assuntos
Lesões Encefálicas , AVC Isquêmico , Humanos , Animais , Bovinos , Suínos , Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Cultura Primária de Células , Técnicas de Cocultura , Astrócitos/metabolismo , Oxigênio/metabolismo , Glucose/metabolismo , Lesões Encefálicas/patologia
12.
Fluids Barriers CNS ; 19(1): 63, 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-35982454

RESUMO

COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. The blood-brain barrier (BBB) was suggested to be the major route of SARS-CoV-2 infection of the brain. Functionally, the BBB is created by an interactome between endothelial cells, pericytes, astrocytes, microglia, and neurons, which form the neurovascular units (NVU). However, at present, the interactions of SARS-CoV-2 with the NVU and the outcomes of this process are largely unknown. Moreover, age was described as one of the most prominent risk factors for hospitalization and deaths, along with other comorbidities such as diabetes and co-infections. This review will discuss the impact of SARS-CoV-2 on the NVU, the expression profile of SARS-CoV-2 receptors in the different cell types of the CNS and the possible role of aging in the neurological outcomes of COVID-19. A special emphasis will be placed on mitochondrial functions because dysfunctional mitochondria are also a strong inducer of inflammatory reactions and the "cytokine storm" associated with SARS-CoV-2 infection. Finally, we will discuss possible drug therapies to treat neural endothelial function in aged patients, and, thus, alleviate the neurological symptoms associated with COVID-19.


Assuntos
COVID-19 , Idoso , Barreira Hematoencefálica , Encéfalo , Células Endoteliais , Humanos , SARS-CoV-2
13.
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.

14.
Res Sq ; 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35734086

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.

15.
Cell Mol Neurobiol ; 42(7): 2131-2146, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34086179

RESUMO

The blood-brain barrier (BBB) is essential for the homeostasis of the central nervous system (CNS). Functions of the BBB are performed by the neurovascular unit (NVU), which consists of endothelial cells, pericytes, astrocytes, microglia, basement membrane, and neurons. NVU cells interact closely and together are responsible for neurovascular coupling, BBB integrity, and transendothelial fluid transport. Studies have shown that NVU dysfunction is implicated in several acute and chronic neurological diseases, including Alzheimer's disease, multiple sclerosis, and stroke. The mechanisms of NVU disruption remain poorly understood, partially due to difficulties in selective targeting of NVU cells. In this review, we discuss the relative merits of available protein markers and drivers of the NVU along with recent advancements that have been made in the field to increase efficiency and specificity of NVU research.


Assuntos
Barreira Hematoencefálica , Células Endoteliais , Astrócitos , Sistema Nervoso Central , Pericitos
16.
Artigo em Inglês | MEDLINE | ID: mdl-36649440

RESUMO

Aim: Elevated brain deposits of amyloid beta (Aß40) contribute to neuropathology and cognitive dysfunction in Alzheimer's disease (AD). However, the role of the blood-brain barrier (BBB) as an interface for the transfer of Aß40 from the periphery into the brain is not well characterized. In addition, a substantial population of neural progenitor cells (NPCs) resides in close proximity to brain capillaries that form the BBB. The aim of this study is to understand the impact of brain endothelium-derived extracellular vesicles (EV) containing Aß40 on metabolic functions and differentiation of NPCs. Methods: Endothelial EVs were derived from an in vitro model of the brain endothelium treated with 100 nM Aß40 or PBS. We then analyzed the impact of these EVs on mitochondrial morphology and bioenergetic disruption of NPCs. In addition, NPCs were differentiated and neurite development upon exposure to EVs was assessed using the IncuCyte Zoom live cell imaging system. Results: We demonstrate that physiological concentrations of Aß40 can be transferred to accumulate in NPCs via endothelial EVs. This transfer results in mitochondrial dysfunction, disrupting crista morphology, metabolic rates, fusion and fission dynamics of NPCs, as well as their neurite development. Conclusion: Intercellular transfer of Aß40 is carried out by brain endothelium-derived EVs, which can affect NPC differentiation and induce mitochondrial dysfunction, leading to aberrant neurogenesis. This has pathological implications because NPCs growing into neurons are incorporated into cerebral structures involved in learning and memory, two common phenotypes affected in AD and related dementias.

17.
Viruses ; 13(9)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34578464

RESUMO

The neurovascular units (NVU) are the minimal functional units of the blood-brain barrier (BBB), composed of endothelial cells, pericytes, astrocytes, microglia, neurons, and the basement membrane. The BBB serves as an important interface for immune communication between the brain and peripheral circulation. Disruption of the NVU by the human immunodeficiency virus-1 (HIV-1) induces dysfunction of the BBB and triggers inflammatory responses, which can lead to the development of neurocognitive impairments collectively known as HIV-1-associated neurocognitive disorders (HAND). Methamphetamine (METH) use disorder is a frequent comorbidity among individuals infected with HIV-1. METH use may be associated not only with rapid HIV-1 disease progression but also with accelerated onset and increased severity of HAND. However, the molecular mechanisms of METH-induced neuronal injury and cognitive impairment in the context of HIV-1 infection are poorly understood. In this review, we summarize recent progress in the signaling pathways mediating synergistic impairment of the BBB and neuronal injury induced by METH and HIV-1, potentially accelerating the onset or severity of HAND in HIV-1-positive METH abusers. We also discuss potential therapies to limit neuroinflammation and NVU damage in HIV-1-infected METH abusers.


Assuntos
Complexo AIDS Demência/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/complicações , Barreira Hematoencefálica/fisiopatologia , Infecções por HIV/complicações , Metanfetamina , Transtornos Neurocognitivos/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Animais , Comorbidade , Infecções por HIV/fisiopatologia , Humanos , Processos Mentais , Doenças Neuroinflamatórias/fisiopatologia
18.
J Neuroinflammation ; 18(1): 167, 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325716

RESUMO

BACKGROUND: Neurological complications are common in patients affected by COVID-19 due to the ability of SARS-CoV-2 to infect brains. While the mechanisms of this process are not fully understood, it has been proposed that SARS-CoV-2 can infect the cells of the neurovascular unit (NVU), which form the blood-brain barrier (BBB). The aim of the current study was to analyze the expression pattern of the main SARS-CoV-2 receptors in naïve and HIV-1-infected cells of the NVU in order to elucidate a possible pathway of the virus entry into the brain and a potential modulatory impact of HIV-1 in this process. METHODS: The gene and protein expression profile of ACE2, TMPRSS2, ADAM17, BSG, DPP4, AGTR2, ANPEP, cathepsin B, and cathepsin L was assessed by qPCR, immunoblotting, and immunostaining, respectively. In addition, we investigated if brain endothelial cells can be affected by the exposure to the S1 subunit of the S protein, the domain responsible for the direct binding of SARS-CoV-2 to the ACE2 receptors. RESULTS: The receptors involved in SARS-CoV-2 infection are co-expressed in the cells of the NVU, especially in astrocytes and microglial cells. These receptors are functionally active as exposure of endothelial cells to the SARS CoV-2 S1 protein subunit altered the expression pattern of tight junction proteins, such as claudin-5 and ZO-1. Additionally, HIV-1 infection upregulated ACE2 and TMPRSS2 expression in brain astrocytes and microglia cells. CONCLUSIONS: These findings provide key insight into SARS-CoV-2 recognition by cells of the NVU and may help to develop possible treatment of CNS complications of COVID-19.


Assuntos
Vasos Sanguíneos/metabolismo , COVID-19/complicações , Infecções por HIV/metabolismo , HIV-1 , Neurônios/metabolismo , Receptores Virais/genética , Receptores Virais/metabolismo , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Astrócitos/metabolismo , Encefalopatias/etiologia , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Microglia/metabolismo , Doenças do Sistema Nervoso/etiologia , Cultura Primária de Células , Receptor Tipo 2 de Angiotensina , Replicação Viral
19.
Res Sq ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33655239

RESUMO

Background. Neurological complications are common in patients affected by COVID-19 due to the ability of SARS-CoV-2 to infect brains. While the mechanisms of this process are not fully understood, it has been proposed that SARS-CoV-2 can infect the cells of the neurovascular units (NVU), which form the blood-brain barrier (BBB). The aim of the current study was to analyze the expression pattern of the main SARS-CoV-2 receptors in naïve and HIV-1-infected cells of the NVU in order to elucidate a possible pathway of the virus entry into the brain and a potential modulatory impact of HIV-1 in this process. Methods. The gene and protein expression profile of ACE2, TMPRSS2, ADAM17, BSG, DPP4, AGTR2, ANPEP, cathepsin B and cathepsin L was assessed by qPCR and immunoblotting, respectively. In addition, we investigated if brain endothelial cells can be affected by the exposure to the S1 subunit of the S protein, the domain responsible for the direct binding of SARS-CoV-2 to the ACE2 receptors. Results. The receptors involved in SARS-CoV-2 infection are coexpressed in the cells of the NVU, especially in astrocytes and microglial cells. These receptors are functionally active as exposure of endothelial cells to the SARS CoV-2 S1 protein subunit altered the expression pattern of tight junction proteins, such as claudin-5 and ZO-1. Additionally, HIV-1 infection upregulated ACE2 and TMPRSS2 expression in brain astrocytes and microglia cells. Conclusions. These findings provide key insight into SARS-CoV-2 recognition by cells of the NVU and may help to develop possible treatment of CNS complications of COVID-19.

20.
Odontoestomatol ; 23(38): e209, 2021. tab, graf
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1340275

RESUMO

Resumen La Clínica de Odontopediatría desarrolla un modelo de atención con énfasis en promoción, educación y rehabilitación destacándose su control y mantenimiento. No hay información sobre el impacto de los controles periódicos. Objetivo: Evaluar la asociación del número de controles y la salud bucal de niños entre 5 y 10 años. Estudio transversal, descriptivo (2017-18) y retrospectivo (hasta 2014) en dos subpoblaciones: G1=controles y G2=primera vez, evaluando diferencias de piezas afectadas Resultados: 115 niños, 44 en G1 y 71 en G2. El 100% presentaron biopelícula. G1 presentó un valor significativamente menor del IPV>20% (p<0.001), de lesiones cavitadas (p<0.001). G1 con 2 o más controles el promedio de lesiones iniciales fue de 2,6 y G2 de 4,5 (p<0.001). Conclusiones: Los niños con dos o más controles presentaron mejor situación de salud bucal que quienes consultaron por primera vez. Se confirma la importancia del control programado para el mantenimiento de la salud bucal.


Resumo A Clínica de Odontologia Pediátrica desenvolve um modelo de cuidado com ênfase na promoção, educação em saúde e reabilitação destacando seu controle e manutenção. Não há informações que sustentem o impacto que os controles regulares. Objetivo: Avaliar a associação do número de controles anuais e da saúde bucal de crianças entre 5 e 10 anos. Estudo transversal e descritivo (2017-18) e retrospectiva (até 2014) em duas subpopulações: G1-controle e G2-primeira vez. Resultados: 115 crianzas: G1-44 e G2-71. 100% do de crianças apresentaram biofilme. G1 apresentou valor de IPV>20% e lesões cavitadas significativamente menor (p<0,001). G1 com 2 ou mais controles a média de lesões iniciais foi de 2,6 e no G2 4,5 (p <0,001). Conclusões: Crianças que assistem a 2 ou mais controles têm uma melhor situação de saúde bucal em comparação com aquelas que consultam pela primeira vez. Confirma-se a importância do controle programado para manutenção da saúde bucal.


Abstract The Pediatric Dentistry Clinic at the School of Dentistry, Universidad de la República, has a care model that focuses on promotion, health education and rehabilitation, and aims to support health control and maintenance. There is no information on the impact of periodic checkups. Objective: To evaluate the association between the number of checkups and oral health in children aged between 5 and 10. Cross-sectional, descriptive (2017-18) and retrospective (up to 2014) study in two subpopulations: G1 = checkups, and G2 = first visit. We evaluated the differences in the number of teeth affected. Results: The sample included 115 children: 44 in G1 and 71 in G2. All of them had biofilm. G1 presented significantly lower values regarding visible plaque index (VPI) (>20%) (p < 0.001) and cavitated lesions (p < 0.001). G1 members, who had attended two or more checkups, had 2.6 initial lesions on average, and G2 members, 4.5 (p < 0.001). Conclusions Children who had attended two or more checkups had better oral health than those seeking care for the first time. This confirms the importance of scheduled checkups for maintaining oral health.

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