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Frontiers in Allergy 2023Epigenetics facilitates insights on the impact of host environment on the genesis of chronic rhinosinusitis (CRS) through modulations of host gene expression and... (Review)
Review
BACKGROUND
Epigenetics facilitates insights on the impact of host environment on the genesis of chronic rhinosinusitis (CRS) through modulations of host gene expression and activity. Epigenetic mechanisms such as DNA methylation cause reversible but heritable changes in gene expression over generations of progeny, without altering the DNA base-pair sequences. These studies offer a critical understanding of the environment-induced changes that result in host predisposition to disease and may help in developing novel biomarkers and therapeutics. The goal of this systematic review is to summarize the current evidence on epigenetics of CRS with a focus on chronic rhinosinusitis with nasal polyps (CRSwNP) and highlight gaps that merit further research.
METHODS
A systematic review of the English language literature was performed to identify investigations related to epigenetic studies in subjects with CRS.
RESULTS
The review identified 65 studies. These have focused on DNA methylation and non-coding RNAs, with only a few on histone deacetylation, alternative polyadenylation, and chromatin accessibility. Studies include those investigating and changes or both. Studies also include animal models of CRS. Almost all have been conducted in Asia. The genome-wide studies of DNA methylation found differences in global methylation between CRSwNP and controls, while others specifically found significant differences in methylation of the CpG sites of the thymic stromal lymphopoietin (), , and . In addition, DNA methyltransferase inhibitors and histone deacetylase inhibitors were studied as potential therapeutic agents. Majority of the studies investigating non-coding RNAs focused on micro-RNAs (miRNA) and found differences in global expression of miRNA levels. These studies also revealed some previously known as well as novel targets and pathways such as tumor necrosis factor alpha, TGF beta-1, IL-10, , aryl hydrocarbon receptor, PI3K/AKT pathway, mucin secretion, and vascular permeability. Overall, the studies have found a dysregulation in pathways/genes involving inflammation, immune regulation, tissue remodeling, structural proteins, mucin secretion, arachidonic acid metabolism, and transcription.
CONCLUSIONS
Epigenetic studies in CRS subjects suggest that there is likely a major impact of the environment. However, these are association studies and do not directly imply pathogenesis. Longitudinal studies in geographically and racially diverse population cohorts are necessary to quantify genetic vs. environmental risks for CRSwNP and CRS without nasal polyps and assess heritability risk, as well as develop novel biomarkers and therapeutic agents.
PubMed: 37284022
DOI: 10.3389/falgy.2023.1165271 -
Infection and Drug Resistance 2022Antigen-presenting cells recognize respiratory syncytial virus antigens, and produce cytokines and chemokines that act on immune cells. Dendritic cells play the main... (Review)
Review
Antigen-presenting cells recognize respiratory syncytial virus antigens, and produce cytokines and chemokines that act on immune cells. Dendritic cells play the main role in inflammatory cytokine responses. Similarly, alveolar macrophages produce IFN-β, IFN-α, TNF-α, IL-6, CXCL10, and CCL3, while alternatively activated macrophages differentiate at the late phase, and require IL-13 or IL-4 cytokines. Furthermore, activated NKT cells secrete IL-13 and IL-4 that cause lung epithelial, endothelial and fibroblasts to secrete eotaxin that enhances the recruitment of eosinophil to the lung. CD8 and CD4T cells infection by the virus decreases the IFN-γ and IL-2 production. Despite this, both are involved in terminating virus replication. CD8T cells produce a larger amount of IFN-γ than CD4T cells, and CD8T cells activated under type 2 conditions produce IL-4, down regulating CD8 expression, granzyme and IFN-γ production. Antiviral inhibitors inhibit biological functions of viral proteins. Some of them directly target the virus replication machinery and are effective at later stages of infection; while others inhibit F protein dependent fusion and syncytium formation. TMC353121 reduces inflammatory cytokines, TNF-α, IL-6, and IL-1β and chemokines, KC, IP-10, MCP and MIP1-α. EDP-938 inhibits viral nucleoprotein (N), while GRP-156784 blocks the activity of respiratory syncytial virus ribonucleic acid (RNA) polymerase. PC786 inhibits non-structural protein 1 (NS-1) gene, RANTES transcripts, virus-induced CCL5, IL-6, and mucin increase. In general, it is an immune reaction that is blamed for the disease severity and pathogenesis in respiratory syncytial virus infection. Anti-viral inhibitors not only inhibit viral entry and replication, but also may reduce inflammatory cytokines and chemokines. Many respiratory syncytial virus inhibitors are proposed; however, only palivizumab and ribavirin are approved for prophylaxis and treatment, respectively. Hence, this review is focused on immunity cell responses to respiratory syncytial virus and the role of antiviral inhibitors.
PubMed: 36540102
DOI: 10.2147/IDR.S387479 -
Heliyon Jul 2023Axenfeld-Rieger Syndrome (ARS) is comprised of a group of autosomal dominant disorders that are each characterized by anterior segment abnormalities of the eye.... (Review)
Review
Axenfeld-Rieger Syndrome (ARS) is comprised of a group of autosomal dominant disorders that are each characterized by anterior segment abnormalities of the eye. Mutations in the transcription factors or are the most well-studied genetic manifestations of this syndrome. Due to the rarity this syndrome, ARS-associated neurological manifestations have not been well characterized. The purpose of this systematic review is to characterize and describe ARS neurologic manifestations that affect the cerebral vasculature and their early and late sequelae. PRISMA guidelines were followed; studies meeting inclusion criteria were analyzed for study design, evidence level, number of patients, patient age, whether the patients were related, genotype, ocular findings, and nervous system findings, specifically neurostructural and neurovascular manifestations. 63 studies met inclusion criteria, 60 (95%) were case studies or case series. The gene was most commonly found, followed by , then . The most commonly described structural neurological findings were white matter abnormalities in 26 (41.3%) of studies, followed by Dandy-Walker Complex 12 (19%), and agenesis of the corpus callosum 11 (17%). Neurovascular findings were examined in 6 (9%) of studies, identifying stroke, cerebral small vessel disease (CSVD), tortuosity/dolichoectasia of arteries, among others, with no mention of moyamoya. This is the first systematic review investigating the genetic, neurological, and neurovascular associations with ARS. Structural neurological manifestations were common, yet often benign, perhaps limiting the utility of MRI screening. Neurovascular abnormalities, specifically stroke and CSVD, were identified in this population. Stroke risk was present in the presence and absence of cardiac comorbidities. These findings suggest a relationship between ARS and neurovascular findings; however, larger scale studies are necessary inform therapeutic decisions.
PubMed: 37539177
DOI: 10.1016/j.heliyon.2023.e18225 -
The Journal of Maternal-fetal &... Dec 2023To estimate the incremental yield of detecting pathogenic or likely pathogenic diagnostic genetic variants (DGV) by whole exome sequencing (WES) over standard karyotype... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To estimate the incremental yield of detecting pathogenic or likely pathogenic diagnostic genetic variants (DGV) by whole exome sequencing (WES) over standard karyotype and chromosomal microarray (CMA) analyses in fetuses with isolated increased nuchal translucency (NT) and normal fetal anatomy at the time of 11-14 weeks scan.
MATERIALS AND METHODS
Medline and Embase databases were searched. Inclusion criteria were fetuses with NT >95 percentile, normal karyotype and CMA and no associated structural anomalies at the time of the 11-14 weeks scan. The primary outcome was to estimate the incremental yield of detecting pathogenic or likely pathogenic genetic variants by WES over standard karyotype and CMA analyses in fetuses with isolated increased nuchal translucency. The secondary outcomes were the detection of a genetic variant of unknown significance. Sub-analysis according to different NT cutoffs (between 3.0 and 5.5 mm and > 5.5 mm) and considering fetuses with isolated NT in which fetal anatomy was confirmed to be normal at the anomaly scan were also performed. Random effects model meta-analyses of proportion were used to analyze the data.
RESULTS
Eight articles (324 fetuses) were included in the systematic review. Of the fetuses with negative standard karyotype and CMA analysis, the 8.07% (95% CI 5.4-11.3) had pathogenic or likely pathogenic genetic variants detected exclusively by WES. When stratifying the analysis according to NT cutoffs, genetic anomalies detected exclusively at WES analysis were found in 44.70% (95% CI 26.8-63.4) of fetuses with NT between 3.0 mm and 5.5 mm and 55.3% (95% CI 36.6-73.2) in those fetuses with NT >5.5 mm and positive WES results. The 7.84% (95% CI 1.6-18.2) had variants of unknown significance identified by WES. When considering fetuses with isolated increased NT and normal fetal anatomy at the anomaly scan, the rate of pathogenic or likely pathogenic genetic variants detected by WES was 3.87% (95% CI 1.6-7.1), while variants of unknown significance were detected in 4.27% (95% CI 2.2-7.0) of cases.
CONCLUSIONS
Pathogenic and likely pathogenic genetic variants detected by WES are present in a significant proportion of fetuses with increased NT but normal standard karyotype and CMA analysis, also when no anomalies are detected at the anomaly scan. Further large studies sharing objective protocols of imaging assessment are needed to confirm these findings and to elucidate which gene panels should be assessed in fetuses with isolated increased NT to rule out associated genetic anomalies, which may potentially impact post-natal outcomes.
Topics: Pregnancy; Female; Humans; Nuchal Translucency Measurement; Exome Sequencing; Fetus; Karyotyping; Karyotype; Prenatal Diagnosis
PubMed: 37019452
DOI: 10.1080/14767058.2023.2193285 -
Frontiers in Cell and Developmental... 2023Circular RNA (circRNA) molecules are noncoding RNAs with ring-like structures formed by covalent bonds and are characterized by no 5caps or polyadenylated tails.... (Review)
Review
Circular RNA (circRNA) molecules are noncoding RNAs with ring-like structures formed by covalent bonds and are characterized by no 5caps or polyadenylated tails. Increasing evidence shows that circRNAs may play an important role in tumorigenesis and cancer metastasis. Circ-SHPRH originates from exons 26-29 of the gene, and it is closely associated with human cancers. We searched PubMed, Web of Science, and Embase databases for relevant literatures until 24 December 2022. Eighteen research papers were included in this review, and 11 papers were selected for meta-analysis after screening. Three eligible published studies about circ-SHPRH were enrolled based on their tumor diagnosis aspect, 7 eligible published studies were related to overall survival (OS), and 3 eligible published studies were related to tumor grade. Many studies have shown that circ-SHPRH acts as a miRNA sponge or encodes a protein to regulate downstream genes or signal pathways, and exerts specific biological functions that affect the proliferation, invasion, and apoptosis of cancer cells. Meta-analysis showed that patients with high expression of circ-SHPRH had better OS (HR = 0.53, 95% CI 0.38-0.74, -value <0.05) and lower TNM stage (HR = 0.33, 95% CI 0.18-0.62, -value = 0.001). In addition, circ-SHPRH has potential diagnostic value (AUC = 0.8357). This review will help enrich our understanding of the role and mechanism of circ-SHPRH in human cancers. Circ-SHPRH has the potential to be a novel diagnostic and prognostic biomarker for various solid cancers.
PubMed: 37305675
DOI: 10.3389/fcell.2023.1182900 -
American Journal of Translational... 2021MicroRNAs (miRNAs) are small non-coding RNAs that participate in gene expression regulation. It has been observed that circulating levels of miRNAs may fluctuate during... (Review)
Review
MicroRNAs (miRNAs) are small non-coding RNAs that participate in gene expression regulation. It has been observed that circulating levels of miRNAs may fluctuate during exercise, showing numerous cardiac biological and physiological effects such as structural and functional adaptations. We aimed to provide an overview of the currently available information concerning the role of circulating miRNAs in cardiovascular adaptations in response to acute and/or chronic exercise training. Relevant studies published were searched in three databases: PubMed, Web of Science and Scopus. A combination of the following keywords was used: ("microRNA" OR "miRNA" OR "miR" AND "exercise" OR "training" OR "physical activity") AND "(heart hypertrophy" OR "cardiac remodeling" OR "cardiac muscle mass" OR "cardiac hypertrophy"). Only experimental studies, written in English and conducted in healthy individuals were included. Five articles met the inclusion criteria and were finally included in this systematic review after reviewing both title, abstract and full-text. A total of thirty-six circulating cardiac-related miRNAs were analyzed, but only five of them (miR-1, miR-133a, miR-146a, miR-206 and miR-221) were directly associated with cardiac adaptations parameters, while two of them (miR-1 and miR-133a) were related to cardiac hypertrophy. Most of them were upregulated immediately after a marathon and returned to basal levels at longer times. Therefore, we conclude that, although evidence is still limited, and long-term studies are needed to obtain more robust evidence, exercise is more likely to affect circulating cardiac-related miRNAs levels.
PubMed: 35035676
DOI: No ID Found -
Journal of Clinical Medicine Oct 2021To determine the diagnostic yield of exome sequencing (ES), a microarray analysis was carried out of fetuses with recurrent fetal structural anomalies (with similar... (Review)
Review
To determine the diagnostic yield of exome sequencing (ES), a microarray analysis was carried out of fetuses with recurrent fetal structural anomalies (with similar anomalies in consecutive pregnancies). This is a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The selected studies describing ES in fetuses with recurrent fetal malformation were assessed using the Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria for risk of bias. Incidence was used as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance). We identified nine studies on ES diagnostic yield that included 140 fetuses with recurrent structural anomalies. A pathogenic or likely pathogenic variant was found in 57 fetuses, resulting in a 40% (95%CI: 26% to 54%) incremental performance pool of ES. As expected, the vast majority (86%: 36/42) of the newly identified diseases had a recessive inheritance pattern, and among these, 42% (15/36) of variants were found in homozygosity. Meckel syndrome was the monogenic disease most frequently found, although the genes involved were diverse. The ES diagnostic yield in pregnancies with recurrent fetal structural anomalies was 40% (57/140). Homozygous disease-causing variants were found in 36% (15/57) of the newly identified monogenic disorders.
PubMed: 34682862
DOI: 10.3390/jcm10204739 -
Folate-Methionine Cycle Disruptions in ASD Patients and Possible Interventions: A Systematic Review.Genes Mar 2023Autism Spectrum Disorder (ASD) has become a major public health concern due to its rapidly rising incidence over the past few years. Disturbances in folate or methionine... (Review)
Review
Autism Spectrum Disorder (ASD) has become a major public health concern due to its rapidly rising incidence over the past few years. Disturbances in folate or methionine metabolism have been identified in many individuals with ASD, suggesting that the folate-methionine cycle may play an essential role in the pathogenesis of autism. Thus, changes in metabolite concentrations associated with this cycle could be used as potential biomarkers and therapeutic targets for ASD. The aim of this systematic review is to elucidate the perturbations of this cycle and the possible interventions that may be proposed in this context. Several studies have shown that high levels of homocysteine and low levels of vitamins B12 and folate are associated with ASD. These changes in serum metabolites are influenced by poor diet. In fact, children with ASD tend to eat selectively, which could compromise the quality of their diet and result in nutrient deficiencies. Moreover, these disturbances may also be caused by genetic predispositions such as polymorphisms of the gene. Few studies have demonstrated the beneficial effects of the use of nutritional supplements in treating ASD children. Therefore, larger, well-structured studies are recommended to examine the impact of vitamin B12 and folate supplementation on homocysteine levels.
Topics: Child; Humans; Folic Acid; Methionine; Autism Spectrum Disorder; Vitamin B 12; Dietary Supplements; Racemethionine
PubMed: 36980981
DOI: 10.3390/genes14030709 -
Frontiers in Genetics 2023Histone variants, which generally differ in few amino acid residues, can replace core histones (H1, H2A, H2B, and H3) to confer specific structural and functional...
Histone variants, which generally differ in few amino acid residues, can replace core histones (H1, H2A, H2B, and H3) to confer specific structural and functional features to regulate cellular functions. In addition to their role in DNA packaging, histones modulate key processes such as gene expression regulation and chromosome segregation, which are frequently dysregulated in cancer cells. During the years, histones variants have gained significant attention as gatekeepers of chromosome stability, raising interest in understanding how structural and functional alterations can contribute to tumourigenesis. Beside the well-established role of the histone H3 variant CENP-A in centromere specification and maintenance, a growing body of literature has described mutations, aberrant expression patterns and post-translational modifications of a variety of histone variants in several cancers, also coining the term "oncohistones." At the molecular level, mechanistic studies have been dissecting the biological mechanisms behind histones and missegregation events, with the potential to uncover novel clinically-relevant targets. In this review, we focus on the current understanding and highlight knowledge gaps of the contribution of histone variants to aneuploidy, and we have compiled a database (HistoPloidyDB) of histone gene alterations linked to aneuploidy in cancers of the The Cancer Genome Atlas project.
PubMed: 38075697
DOI: 10.3389/fgene.2023.1290903 -
Advanced Drug Delivery Reviews 2020Advances in medical science have led to diverse new therapeutic modalities, as well as enhanced understanding of the progression of various disease states. These...
Advances in medical science have led to diverse new therapeutic modalities, as well as enhanced understanding of the progression of various disease states. These findings facilitate the design and development of more customized and exquisite drug delivery systems that aim to improve therapeutic indices of drugs to treat a variety of conditions. Synthetic polymer-based drug carriers have often been the focus of such research. However, these structures suffer from challenges with heterogeneity of the starting material, limited chemical features, complex functionalization methods, and in some cases a lack of biocompatibility. Consequently, protein-based polymers have garnered much attention in recent years due to their monodisperse features, ease of production and functionalization, and biocompatibility. Genetic engineering techniques enable the advancement of protein-based drug delivery systems with finely tuned physicochemical properties, and thus an expanded level of customization unavailable with synthetic polymers. Of these genetically engineered proteins, elastin-like proteins (ELP), silk-like proteins (SLP), and silk-elastin-like proteins (SELP) provide a unique set of alternatives for designing drug delivery systems due to their inherent chemical and physical properties and ease of engineering afforded by recombinant DNA technologies. In this review we examine the advantages of genetically engineered drug delivery systems with emphasis on ELP and SLP constructions. Methods for fabrication and relevant biomedical applications will also be discussed.
Topics: Biocompatible Materials; Drug Delivery Systems; Elastin; Gene Transfer Techniques; Humans; Hydrogels; Nanoparticles; Particle Size; Protein Engineering; Recombinant Proteins; Silk
PubMed: 33080258
DOI: 10.1016/j.addr.2020.10.008