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.
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.
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.
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.
Mutations in the lamin A/C gene (LMNA) cause dilated cardiomyopathy associated with increased activity of ERK1/2 in the heart. We recently showed that ERK1/2 phosphorylates cofilin-1 on threonine 25 ...(phospho(T25)-cofilin-1) that in turn disassembles the actin cytoskeleton. Here, we show that in muscle cells carrying a cardiomyopathy-causing LMNA mutation, phospho(T25)-cofilin-1 binds to myocardin-related transcription factor A (MRTF-A) in the cytoplasm, thus preventing the stimulation of serum response factor (SRF) in the nucleus. Inhibiting the MRTF-A/SRF axis leads to decreased α-tubulin acetylation by reducing the expression of ATAT1 gene encoding α-tubulin acetyltransferase 1. Hence, tubulin acetylation is decreased in cardiomyocytes derived from male patients with LMNA mutations and in heart and isolated cardiomyocytes from Lmna
male mice. In Atat1 knockout mice, deficient for acetylated α-tubulin, we observe left ventricular dilation and mislocalization of Connexin 43 (Cx43) in heart. Increasing α-tubulin acetylation levels in Lmna
mice with tubastatin A treatment restores the proper localization of Cx43 and improves cardiac function. In summary, we show for the first time an actin-microtubule cytoskeletal interplay mediated by cofilin-1 and MRTF-A/SRF, promoting the dilated cardiomyopathy caused by LMNA mutations. Our findings suggest that modulating α-tubulin acetylation levels is a feasible strategy for improving cardiac function.
There are certain critical periods during pregnancy when the fetus is at high risk for exposure to teratogens. Some microorganisms, including
, are known to exhibit teratogenic effects, interfering ...with fetal development and causing irreversible disturbances.
is an obligate intracellular parasite and the etiological agent of Toxoplasmosis, a zoonosis that affects one third of the world's population. Although congenital infection can cause severe fetal damage, the injury extension depends on the gestational period of infection, among other factors, like parasite genotype and host immunity. This parasite invades the Central Nervous System (CNS), forming tissue cysts, and can interfere with neurodevelopment, leading to frequent neurological abnormalities associated with
infection. Therefore,
is included in the
complex of infectious diseases that may lead to neurological malformations (
oxoplasmosis,
thers,
ubella,
ytomegalovirus, and
erpes). The retina is part of CNS, as it is derived from the diencephalon. Except for astrocytes and microglia, retinal cells originate from multipotent neural progenitors. After cell cycle exit, cells migrate to specific layers, undergo morphological and neurochemical differentiation, form synapses and establish their circuits. The retina is organized in nuclear layers intercalated by plexus, responsible for translating and preprocessing light stimuli and for sending this information to the brain visual nuclei for image perception. Ocular toxoplasmosis (OT) is a very debilitating condition and may present high severity in areas in which virulent strains are found. However, little is known about the effect of congenital infection on the biology of retinal progenitors/ immature cells and how this infection may affect the development of this tissue. In this context, this study reviews the effects that congenital infections may cause to the developing retina and the cellular and molecular aspects of these diseases, with special focus on congenital OT.
Yeast infections have gained significant attention in the field of marine biology in recent years. Among the broad diversity of marine organisms affected by these infections, elasmobranchs (sharks ...and rays) have emerged as highly susceptible, due to climate change effects, such as increasing water temperatures and pollution, which can alter the composition and abundance of fungal communities. Additionally, injuries, or compromised immune systems resulting from pollution or disease may increase the likelihood of fungal infections in elasmobranchs. Studies are, however, still lacking for this taxonomic group. In this context, this study aimed to screen yeast species in cell cultures obtained from the brain of artisanally captured Pseudobatos horkelii, a cartilaginous fish that, although endangered, is highly captured and consumed worldwide. Fungi were isolated during an attempt to establish primary cultures of elasmobranch neural cells. Culture flasks were swabbed and investigated using morphological, phenotypic, and molecular techniques. Two isolates of the emerging opportunistic pathogen Trichosporon japonicum were identified, with high scores (1.80 and 1.85, respectively) by the MALDI-ToF technique. This is the first report of the basidiomycetous yeast T. japonicum in Pseudobatos horkelii in Brazil. This finding highlights the need for further research to determine the potential impact on elasmobranch health, ecology, as well as on commercial fisheries.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
•Evidence on the global gene expression of periodontal cells under static loading is scarce.•The studies on the subject show great heterogeneity in the methods implemented.•Definitive conclusions on ...differentially expressed molecular pathways during orthodontic tooth movement are not yet possible.
To evaluate the evidence reporting gene expression array data of human in vitro cultured periodontal ligament cells (PDLCs) submitted to static mechanical loading compared to a control group.
Systematic searches were performed in MEDLINE/PubMed, Scopus, Web of Science, Virtual Health Library, The Cochrane Library and the System for Information on Grey Literature in Europe up to June 2019. A narrative synthesis was performed to summarize differentially expressed genes (DEGs). These were grouped according to the culture method (2D or 3D), force type (compression or tension) and observation time. Additionally, gene ontology (GO) analysis was performed using the Database for Annotation Visualization and Integrated Discovery. The risk of bias (RoB) and certainty of evidence (CoE) were assessed using a modified CONSORT checklist and the GRADE tool, respectively.
Of eight studies included (all rated as having moderate RoB), only two provided the complete list of DEGs and four studies performed GO, gene network or pathways analysis. “Cell proliferation”, “cell-cell signaling”, “response to hypoxia and to mechanical stimulus” were among the significantly enriched biological processes in 3D-cultured compressed PDLCs (moderate CoE); while “collagen catabolic process”, “extracellular matrix organization” and “cell proliferation” were associated with DEGs of 3D-cultured PDLCs submitted to tension (very low CoE). Biological processes significantly enriched in 2D-cultured PDLCs under compression were “extracellular matrix organization”, “canonical glycolysis” and “glycolytic process” (very low CoE).
Genes such as NR4A2, NR4A3, NAMPT, PGK1, and REDD1 are suggested as novel biomarkers for orthodontic tooth movement. Limited amount of evidence on the complete gene expression profile and the high heterogeneity in methodologies make it impossible to obtain definite conclusions. New studies following standardized and well-designed in vitro model and reporting complete gene expression datasets are needed.
Toxoplasmosis affects one third of the world population and has the protozoan
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.
Pregnant females of pigmented C57BL/6 strain mice were infected intragastrically with two
cysts (ME49 strain) at embryonic day 10 (E10), and the offspring were analyzed at E18.
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 β-III-tubulin-positive cells, one of the earliest markers of neuronal differentiation.
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.
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.
Cardiac physiology depends on coupling and electrical and mechanical coordination through the intercalated disc. Focal adhesions offer mechanical support and signal transduction events during heart ...contraction-relaxation processes. Talin links integrins to the actin cytoskeleton and serves as a scaffold for the recruitment of other proteins, such as paxillin in focal adhesion formation and regulation. Chagasic cardiomyopathy is caused by infection by Trypanosoma cruzi and is a debilitating condition comprising extensive fibrosis, inflammation, cardiac hypertrophy and electrical alterations that culminate in heart failure.
Since mechanotransduction coordinates heart function, we evaluated the underlying mechanism implicated in the mechanical changes, focusing especially in mechanosensitive proteins and related signalling pathways during infection of cardiac cells by T. cruzi.
We investigated the effect of T. cruzi infection on the expression and distribution of talin/paxillin and associated proteins in mouse cardiomyocytes in vitro by western blotting, immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR).
Talin and paxillin spatial distribution in T. cruzi-infected cardiomyocytes in vitro were altered associated with a downregulation of these proteins and mRNAs levels at 72 h post-infection (hpi). Additionally, we observed an increase in the activation of the focal adhesion kinase (FAK) concomitant with increase in β-1-integrin at 24 hpi. Finally, we detected a decrease in the activation of FAK at 72 hpi in T. cruzi-infected cultures.
The results suggest that these changes may contribute to the mechanotransduction disturbance evidenced in chagasic cardiomyopathy.
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.
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