Dataset Information

Dysregulation of human miRNAs and increased prevalence of HHV miRNAs in obese periodontitis subjects.

ABSTRACT: AIM:To evaluate human and herpesvirus-encoded microRNA (miRNA) expression in healthy and diseased gingiva of obese and non-obese subjects and compare the impact of localized and systemic inflammation on human miRNA profiles. MATERIAL AND METHODS:Healthy and inflamed gingival biopsies were collected from obese and non-obese subjects. Human and herpesvirus miRNA expression was quantified using quantitative PCR. Predicted targets of dysregulated miRNAs were identified using bioinformatics analysis, validated by dual luciferase assays and their expression assessed in healthy and diseased tissues. RESULTS:Our results show differential expression of miRNAs in both diseased groups compared to healthy counterparts. MMP-16 is identified as a novel target of miRNAs altered in disease. Expression analysis of genes predicted as target of differentially expressed miRNAs show significant changes in disease compared with healthy tissues. Finally, quantitation of four herpesvirus-derived viral miRNAs show that the expression and prevalence of herpesvirus miRNAs in diseased gingiva of obese subjects. CONCLUSION:Our findings show that miRNA (both cellular and virus) expression is differentially responsive to local and systemic inflammation. Some of these miRNAs can modulate key cellular genes with direct consequences on inflammatory pathways suggesting their impact on oral tissue transcriptome and functions.

SUBMITTER: Naqvi AR

PROVIDER: S-EPMC6340734 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Dysregulation of human miRNAs and increased prevalence of HHV miRNAs in obese periodontitis subjects.

Naqvi Afsar R AR Brambila Maria F MF Martínez Gloria G Chapa Gabriela G Nares Salvador S

Journal of clinical periodontology 20190101 1

<h4>Aim</h4>To evaluate human and herpesvirus-encoded microRNA (miRNA) expression in healthy and diseased gingiva of obese and non-obese subjects and compare the impact of localized and systemic inflammation on human miRNA profiles.<h4>Material and methods</h4>Healthy and inflamed gingival biopsies were collected from obese and non-obese subjects. Human and herpesvirus miRNA expression was quantified using quantitative PCR. Predicted targets of dysregulated miRNAs were identified using bioinform ...[more]

PMID: 30499589

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Project description:Increased local immune and inflammatory responses in obese individuals with periodontitis may explain the aggressive clinical presentation and altered treatment response when compared to that of normal weight subjects. Our goal was to identify any differences in microRNA (miRNA) expression profiles of gingival tissue in periodontitis when obesity is present, which may suggest novel molecular pathways that this miRNA network may affect. Total RNA was extracted from gingival tissue biopsies collected from normal weight and obese individuals with periodontitis; miRNA expression profiling was performed with Affymetrix GeneChip miRNA 3.0 arrays; and results were validated with quantitative reverse transcription polymerase chain reaction (qRT-PCR). In silico identification of previously confirmed miRNA gene targets was conducted through miRTarBase and miRWalk databases, and pathway enrichment analysis identified enriched miRNA gene sets. Expression of selected genes in the same biopsy samples was tested with qRT-PCR. The gingival tissue miRNA profile of obese patients, compared to that of normal weight patients, showed 13 upregulated and 22 downregulated miRNAs, among which miR-200b was validated by qRT-PCR to be significantly increased in obesity. Functional analysis of 51 experimentally validated miR-200b gene targets identified enrichment of genes involved in cell motility, differentiation, DNA binding, response to stimulus, and vasculature development pathways not previously identified in the obesity-specific disease profile. Furthermore, the expression of the miR-200b gene targets ZEB1/2, GATA2, and KDR was confirmed by qRT-PCR as being lower in obese patients with periodontitis versus normal weight patients, suggesting a role of miR-200b in regulation of a set of gene targets and biological pathways relevant to wound healing and angiogenesis. Functional studies to explore the role of miR-200b in the above processes may offer new insights on putative therapeutic targets for this group of patients.

Project description:ObjectiveEndothelial adhesion molecules like E-selectin play an important role in leukocyte recruitment and development of atherosclerotic plaque. E-selectin is increased in obesity, yet little is known regarding the specific factors contributing to elevated E-selectin in obesity and whether tumour necrosis factor alpha (TNF-alpha) increases E-selectin in vivo in this population. The objectives of this study were to: (1) determine the body composition, metabolic and inflammatory factors associated with increased E-selectin and (2) determine the role of TNF-alpha in the physiological regulation of E-selectin by antagonism of TNF-alpha with etanercept among obese subjects.MethodsE-selectin levels, body composition, metabolic parameters and inflammatory cytokines were assessed in 51 obese subjects and 37 non-obese healthy controls. Obese subjects were randomized to etanercept 50 mg weekly or placebo for 4 weeks. Changes in E-selectin were compared between treatment groups.ResultsObese subjects had higher E-selectin than non-obese controls (47.4 [32.7-58.8] vs. 27.2 [20.3-42.1] ng/ml, obese vs. non-obese, P < 0.0001). E-selectin was significantly associated with multiple body composition measures and metabolic parameters, along with specific measures of TNF-alpha activation, including soluble tumour necrosis factor receptors 1 (P = 0.03) and 2 (P = 0.02). In multivariate modelling, visceral adipose tissue, but not other measures of body composition, remained significantly associated with E-selectin. Among obese subjects, treatment with etanercept significantly decreased E-selectin (-5.7+/- 8.7 vs. 0.5+/- 6.0 ng/ml, etanercept vs. placebo, P = 0.005).ConclusionsE-selectin is increased in obesity, in relationship to increased visceral adiposity and markers of TNF-alpha activation. TNF-alpha antagonism with etanercept reduces E-selectin in obese subjects, providing evidence that the systemic circulatory release of E-selectin is regulated at least in part by TNF-alpha in obesity.

Project description:Obstructive sleep apnea (OSA) is prevalent in obese subjects. Plasma adiponectin level in obese subjects is decreased. Whether reduced adiponectin level is associated with OSA is unknown. Participants without a previous diagnosis of OSA or who have not been treated with continuous positive airway pressure were enrolled and parameters of interest were collected. Polysomnography was performed to evaluate the presence of OSA and the severity of OSA as indexed by the apnea-hypopnea index (AHI). Between-group differences were analyzed. Pearson correlation analysis was used to evaluate the association between body mass index (BMI) with plasma levels of adiponectin and C-reactive protein (CRP) and AHI; and the association between plasma adiponectin level with CRP and AHI was also evaluated. Logistic regression analysis was conducted to evaluate the association between per 1-SD standardized decrease of plasma adiponectin level and the prevalence of OSA using stepwise adjustment models. A total of 486 participants were enrolled and the mean BMI was 26.9 ± 6.2 kg/m with obesity prevalence of 28%; and the mean AHI was 12.6 ± 8.9 per sleep hour with OSA prevalence of 42%. The mean adiponectin level was 18.4 ± 10.6 μg/mL. Compared with the nonobese group, participants in the obese group had higher BMI, neck girth, waist circumference, and AHI (P < .05 for all comparisons). The prevalence of OSA (51% vs 37%) and the proportion of moderate OSA (49% vs 42%) were also significantly higher, while adiponectin level (14.6 ± 8.7 μg/mL vs 20.7 ± 10.5 μg/mL) was significantly lower. In the obese group, plasma adiponectin level was decreased gradually with the increasing severity of OSA, which was not observed in the nonobese group. BMI was negatively correlated with adiponectin while positively correlated with CRP and AHI; and adiponectin was negatively correlated with both CRP and AHI. After adjusted for covariates including BMI and waist circumference, adiponectin remained significantly associated with OSA prevalence with odds ratio of 1.20 (95% confidence interval 1.12-1.65). In summary, our preliminary study suggests that in obese subjects, plasma adiponectin level is associated with the prevalence of OSA.

Project description:Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there are only three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscore the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in several nervous system disorders (e.g., multiple sclerosis, epilepsy, and chronic fatigue syndrome), the mechanisms of action and relative contributions of each virus to neurological dysfunction are unclear. Unresolved questions regarding differences in cell tropism, receptor use and binding affinity (i.e., CD46 versus CD134), host neuro-immunological responses, and relative virulence between HHV-6A versus HHV-6B prevent a complete characterization. Although it has been shown that both HHV-6A and HHV-6B can infect glia (and, recently, cerebellar Purkinje cells), cell tropism of HHV-6A versus HHV-6B for different nerve cell types remains vague. In this study, we show that both viruses can infect different nerve cell types (i.e., glia versus neurons) and different neurotransmitter phenotypes derived from differentiated human neural stem cells. As demonstrated by immunofluorescence, HHV-6A and HHV-6B productively infect VGluT1-containing cells (i.e., glutamatergic neurons) and dopamine-containing cells (i.e., dopaminergic neurons). However, neither virus appears to infect GAD67-containing cells (i.e., GABAergic neurons). As determined by qPCR, expression of immunological factors (e.g., cytokines) in cells infected with HHV-6A versus HHV6-B also differs. These data along with morphometric and image analyses of infected differentiated neural stem cell cultures indicate that while HHV-6B may have greater opportunity for transmission, HHV-6A induces more severe cytopathic effects (e.g., syncytia) at the same post-infection end points. Cumulatively, results suggest that HHV-6A is more virulent than HHV-6B in susceptible cells, while neither virus productively infects GABAergic cells. Consistency between these in vitro data and in vivo experiments would provide new insights into potential mechanisms for HHV6-induced epileptogenesis.

Dataset Information

Dysregulation of human miRNAs and increased prevalence of HHV miRNAs in obese periodontitis subjects.

Publications

Dysregulation of human miRNAs and increased prevalence of HHV miRNAs in obese periodontitis subjects.

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