New candidate genes potentially involved in Zika virus teratogenesis.

Despite efforts to elucidate Zika virus (ZIKV) teratogenesis, still several issues remain unresolved, particularly on the molecular mechanisms behind the pathogenesis of Congenital Zika Syndrome (CZS). To answer this question, we used bioinformatics tools, animal experiments and human gene expression analysis to investigate genes related to brain development potentially involved in CZS. Searches in databases for genes related to brain development and CZS were performed, and a protein interaction network was created.

Bioinformatics Methods for Transcriptome Analysis on Teratogenesis Testing.

Teratogenesis testing can be challenging due to the limitations of both in vitro and in vivo models. Test-systems, based especially on human embryonic cells, have been helping to overcome the difficulties when allied to omics strategies, such as transcriptomics. In these test-systems, cells exposed to different compounds are then analyzed in microarray or RNA-seq platforms regarding the impacts of the potential teratogens in the gene expression.

A New Strategy for the Old Challenge of Thalidomide: Systems Biology Prioritization of Potential Immunomodulatory Drug (IMiD)-Targeted Transcription Factors.

Several molecular mechanisms of thalidomide embryopathy (TE) have been investigated, from anti-angiogenesis to oxidative stress to cereblon binding. Recently, it was discovered that thalidomide and its analogs, named immunomodulatory drugs (IMiDs), induced the degradation of C2H2 transcription factors (TFs). This mechanism might impact the strict transcriptional regulation of the developing embryo.

Genetic evaluation of HAND2 gene and its effects on thalidomide embryopathy.

Background: HAND2 is a transcription factor important for embryonic development, required for limbs and cardiovascular development. Thalidomide is a drug responsible to a spectrum of congenital anomalies known as Thalidomide Embryopathy (TE), which includes mainly limb and heart defects. It is known that HAND2 interaction with TBX5, an important protein for limbs and heart development, is inhibited by Thalidomide.

Transcriptome meta-analysis of valproic acid exposure in human embryonic stem cells.

Valproic acid (VPA) is a widely used antiepileptic drug not recommended in pregnancy because it is teratogenic. Many assays have assessed the impact of the VPA exposure on the transcriptome of human embryonic stem-cells (hESC), but the molecular perturbations that VPA exerts in neurodevelopment are not completely understood. This study aimed to perform a transcriptome meta-analysis of VPA-exposed hESC to elucidate the main biological mechanisms altered by VPA effects on the gene expression.

Neurodevelopment in Children Exposed to Zika : Clinical and Molecular Aspects.

Five years after the identification of Zika virus as a human teratogen, we reviewed the early clinical manifestations, collectively called congenital Zika syndrome (CZS). Children with CZS have a very poor prognosis with extremely low performance in motor, cognitive, and language development domains, and practically all feature severe forms of cerebral palsy. However, these manifestations are the tip of the iceberg, with some children presenting milder forms of deficits.

National congenital anomaly registers in the world: historical and operational aspects.

Objective: To identify registers of congenital anomalies with national coverage currently available around the world, highlighting their main historical and operational characteristics.

Methods: This was a documentary study by means of a Medline database search (via PubMed) and searches involving reports, official documents and websites. Studies reporting at least one national registry were included.

Comparative Genomics Identifies Putative Interspecies Mechanisms Underlying Crbn-Sall4-Linked Thalidomide Embryopathy.

The identification of thalidomide-Cereblon-induced SALL4 degradation has brought new understanding for thalidomide embryopathy (TE) differences across species. Some questions, however, regarding species variability, still remain. The aim of this study was to detect sequence divergences between species, affected or not by TE, and to evaluate the regulated gene co-expression in a murine model.

Molecular mechanisms of Zika virus teratogenesis from animal studies: a systematic review protocol.

Background: Due to the diversity of studies in animal models reporting that molecular mechanisms are involved in the teratogenic effect of the Zika virus (ZIKV), the objective of the present study is to evaluate the methodological quality of these studies, as well as to demonstrate which genes and which molecular pathways are affected by ZIKV in different animal models.

Methods: This search will be performed in four databases: PubMed/MEDLINE, EMBASE, Web of Science, and Scopus, as well as in the grey literature. The studies selection process will be reported through the PRISMA Statement diagram model.

Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation.

Embryofetal development is a critical process that needs a strict epigenetic control, however, perturbations in this balance might lead to the occurrence of congenital anomalies. It is known that anticonvulsants potentially affect epigenetics-related genes, however, it is not comprehended whether this unbalance could explain the anticonvulsants-induced fetal syndromes. In the present study, we aimed to evaluate the expression of epigenetics-related genes in valproic acid, carbamazepine, or phenytoin exposure.

CRL4-Cereblon complex in Thalidomide Embryopathy: a translational investigation.

The Cereblon-CRL4 complex has been studied predominantly with regards to thalidomide treatment of multiple myeloma. Nevertheless, the role of Cereblon-CRL4 in Thalidomide Embryopathy (TE) is still not understood. Not all embryos exposed to thalidomide develop TE, hence here we evaluate the role of the CRL4-Cereblon complex in TE variability and susceptibility.

The role of ESCO2, SALL4 and TBX5 genes in the susceptibility to thalidomide teratogenesis.

Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes.

Assembling systems biology, embryo development and teratogenesis: What do we know so far and where to go next?

The recognition of molecular mechanisms of a teratogen can provide insights to understand its embryopathy, and later to plan strategies for the prevention of new exposures. In this context, experimental research is the most invested approach. Despite its relevance, these assays require financial and time investment.

Zika Virus as a Possible Risk Factor for Autism Spectrum Disorder: Neuroimmunological Aspects.

The recent outbreak of the Zika virus (ZIKV) and the discovery that perinatal Zika exposure can lead to the Congenital Zika Syndrome has promoted a call for prevention measures. Due to the increased number of babies born with microcephaly, structural brain abnormalities, and neurological alterations in regions affected by ZIKV, investigations were carried out in order to better understand this process. The maternal immune system directly influences the fetal central nervous system, and complications during pregnancy have been associated with neurodevelopmental disorders.

Genetic susceptibility to thalidomide embryopathy in humans: Study of candidate development genes.

Thalidomide is a drug used worldwide for several indications, but the molecular mechanisms of its teratogenic property are not fully understood. Studies in animal models suggest the oxidative stress, the inhibition of angiogenesis, and the binding to E3-ubiquitin ligase complex as mechanisms by which thalidomide can change the expression of genes important to embryonic development. In this study, seven polymorphisms in genes related to development (FGF8, FGF10, BMP4, SHH, TP53, TP63, and TP73) were analyzed in people with thalidomide embryopathy (TE) and compared to people without malformations.

Plasma matrix metalloproteinase-9 levels predict intensive care unit mortality early after severe traumatic brain injury.

Objectives: Matrix metalloproteinase-9 (MMP-9) is an inducible metalloproteinase that can degrade the cerebrovascular matrix leading to disruption of the blood-brain barrier and exacerbation of oedema in neurotrauma. Therefore, our aim was to determine whether MMP-9 plasma levels were associated with intensive care unit (ICU) mortality after severe traumatic brain injury (TBI) despite the presence of extracerebral injuries.

Methods: This cohort enrolled 80 patients who suffered severe TBI (Glasgow Coma Scale: 3-8 at hospital admission).