ABSTRACT
Extracellular vesicles (EVs) are a new mechanism of cellular communication, by delivering their cargo into target cells to modulate molecular pathways. EV-mediated crosstalk contributes to tumor survival and resistance to cellular stress. However, the role of EVs in B-cell Acute Lymphoblastic Leukaemia (B-ALL) awaits to be thoroughly investigated. We recently published that ActivinA increases intracellular calcium levels and promotes actin polymerization in B-ALL cells. These biological processes guide cytoskeleton reorganization, which is a crucial event for EV secretion and internalization. Hence, we investigated the role of EVs in the context of B-ALL and the impact of ActivinA on this phenomenon. We demonstrated that leukemic cells release a higher number of EVs in response to ActivinA treatment, and they can actively uptake EVs released by other B-ALL cells. Under culture-induced stress conditions, EVs coculture promoted cell survival in B-ALL cells in a dose-dependent manner. Direct stimulation of B-ALL cells with ActivinA or with EVs isolated from ActivinA-stimulated cells was even more effective in preventing cell death. This effect can be possibly ascribed to the increase of vesiculation and modifications of EV-associated microRNAs induced by ActivinA. These data demonstrate that ActivinA boosts EV-mediated B-ALL crosstalk, improving leukemia survival in stress conditions.
Subject(s)
Cell Communication , Cell Survival , Extracellular Vesicles , Extracellular Vesicles/metabolism , Humans , Cell Line, Tumor , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , MicroRNAs/metabolism , MicroRNAs/geneticsABSTRACT
Introduction: Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB). Metabolomics might represent a valuable tool to reveal the biochemical mechanisms/pathways underlying clinical differences between PWS and EOB. The aim of the present (case-control, retrospective) study was to determine the metabolomic profile that characterizes PWS compared to EOB. Methods: A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to measure a total of 188 endogenous metabolites in plasma samples of 32 patients with PWS (F/M = 23/9; age: 31.6 ± 9.2 years; body mass index [BMI]: 42.1 ± 7.0 kg/m2), compared to a sex-, age- and BMI-matched group of patients with EOB (F/M = 23/9; age: 31.4 ± 6.9 years; BMI: 43.5 ± 3.5 kg/m2). Results: Body composition in PWS was different when compared to EOB, with increased fat mass and decreased fat-free mass. Glycemia and HDL cholesterol were higher in patients with PWS than in those with EOB, while insulinemia was lower, as well as heart rate. Resting energy expenditure was lower in the group with PWS than in the one with EOB, a difference that was missed after fat-free mass correction. Carrying out a series of Tobit multivariable linear regressions, adjusted for sex, diastolic blood pressure, and C reactive protein, a total of 28 metabolites was found to be associated with PWS (vs. non-PWS, i.e., EOB), including 9 phosphatidylcholines (PCs) ae, 5 PCs aa, all PCs aa, 7 lysoPCs a, all lysoPCs, 4 acetylcarnitines, and 1 sphingomyelin, all of which were higher in PWS than EOB. Conclusions: PWS exhibits a specific metabolomic profile when compared to EOB, suggesting a different regulation of some biochemical pathways, fundamentally related to lipid metabolism.
Subject(s)
Metabolomics , Prader-Willi Syndrome , Humans , Prader-Willi Syndrome/metabolism , Prader-Willi Syndrome/blood , Female , Male , Adult , Metabolomics/methods , Case-Control Studies , Retrospective Studies , Obesity, Morbid/metabolism , Obesity, Morbid/blood , Metabolome , Young Adult , Body Mass Index , Body Composition , Chromatography, Liquid , Tandem Mass SpectrometryABSTRACT
Acute kidney injury (AKI) is common in hospitalized patients and increases short-term and long-term mortality. Treatment options for AKI are limited. Gut microbiota products such as the short-chain fatty acid butyrate have anti-inflammatory actions that may protect tissues, including the kidney, from injury. However, the molecular mechanisms of tissue protection by butyrate are poorly understood. Treatment with oral butyrate for two weeks prior to folic acid-induced AKI and during AKI improved kidney function and decreased tubular injury and kidney inflammation while stopping butyrate before AKI was not protective. Continuous butyrate preserved the expression of kidney protective factors such as Klotho, PGC-1α and Nlrp6 which were otherwise downregulated. In cultured tubular cells, butyrate blunted the maladaptive tubular cell response to a proinflammatory milieu, preserving the expression of kidney protective factors. Kidney protection afforded by this continuous butyrate schedule was confirmed in a second model of nephrotoxic AKI, cisplatin nephrotoxicity, where the expression of kidney protective factors was also preserved. To assess the contribution of preservation of kidney protective factors to kidney resilience, recombinant Klotho was administered to mice with cisplatin-AKI and shown to preserve the expression of PGC-1α and Nlrp6, decrease kidney inflammation and protect from AKI. In conclusion, butyrate promotes kidney resilience to AKI and decreases inflammation by preventing the downregulation of kidney protective genes such as Klotho. This information may be relevant to optimize antibiotic management during hospitalization.
Subject(s)
Acute Kidney Injury , Butyrates , Mice, Inbred C57BL , Animals , Acute Kidney Injury/chemically induced , Acute Kidney Injury/metabolism , Acute Kidney Injury/prevention & control , Mice , Butyrates/pharmacology , Male , Humans , Kidney Tubules/drug effects , Kidney Tubules/metabolism , Cisplatin/toxicity , Cisplatin/adverse effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Klotho ProteinsABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0261591.].
ABSTRACT
Intercellular communication has been transformed by the discovery of extracellular vesicles (EVs) and their cargo, including microRNAs (miRNAs), which play crucial roles in intercellular signaling. These EVs were previously disregarded as cellular debris but are now recognized as vital mediators of biological information transfer between cells. Furthermore, they respond not only to internal stimuli but also to environmental and lifestyle factors. Identifying EV-borne oncomiRs, a subset of miRNAs implicated in cancer development, could revolutionize our understanding of how environmental and lifestyle exposures contribute to oncogenesis. To investigate this, we studied the plasma levels of EV-borne oncomiRs in a population of 673 women and 238 men with a body mass index > 25 kg/m2 (SPHERE population). The top fifty oncomiRs associated with the three most common cancers in women (breast, colorectal, and lung carcinomas) and men (lung, prostate, and colorectal carcinomas) were selected from the OncomiR database. Only oncomiRs expressed in more than 20% of the population were considered for statistical analysis. Using a Multivariate Adaptive Regression Splines (MARS) model, we explored the interactions between environmental/lifestyle exposures and EV oncomiRs to develop optimized predictor combinations for each EV oncomiR. This innovative approach allowed us to better understand miRNA regulation in response to multiple environmental and lifestyle influences. By uncovering non-linear relationships among variables, we gained valuable insights into the complexity of miRNA regulatory networks. Ultimately, this research paves the way for comprehensive exposome studies in the future.
ABSTRACT
Human endogenous retroviruses (HERVs) are transposable genomic elements generally repressed through DNA methylation. HERVs can be demethylated and expressed in response to environmental stimuli. Therefore, more research is needed to understand the influence of environmental exposures on HERV methylation. Air pollutants are commonly linked with global hypomethylation, and as HERVs comprise of nearly 8% of repetitive elements in the human genome, our objective was to examine the association between air pollutant exposure and HERV methylation. We investigated 180 students with asthma participating in the School Inner-City Asthma Intervention Study, which evaluated the efficacy of classroom air filters and school-wide pest management on air pollutant/allergen exposure and asthma. Both air pollutants measured in classrooms and asthma outcomes assessed by surveys were collected pre- and post-intervention. Buccal swabs were also collected pre- and post-intervention, and methylation levels from 9 transposable genomic elements (HERV-E, -FRD, -K, -L, -R, -W, -9, and HRES and LINE1) were measured. Adjusting for relevant covariates, the overall air pollutant mixture was cross-sectionally associated with higher HERV-W and lower HERV-L and LINE1 methylation. Coarse PM was cross-sectionally associated with higher HERV-K methylation and CO2 with lower LINE1 methylation. These results suggest that exposure to air pollutants is associated with HERV-W and HERV-K hypermethylation and HERV-L and LINE1 hypomethylation in children with asthma. Future studies are needed to characterize the links between HERV methylation and possible adverse outcomes.
Subject(s)
Air Pollutants , Air Pollution , Asthma , Endogenous Retroviruses , Child , Humans , Endogenous Retroviruses/genetics , DNA Methylation , Air Pollutants/toxicity , Schools , Air Pollution/adverse effects , Asthma/geneticsABSTRACT
Circadian rhythms are generated by a series of genes, collectively named clock genes, which act as a self-sustained internal 24 h timing system in the body. Many physiological processes, including metabolism and the endocrine system, are regulated by clock genes in coordination with environmental cues. Loss of the circadian rhythms has been reported to contribute to widespread obesity, particularly in the pediatric population, which is increasingly exposed to chronodisruptors in industrialized society. The aim of the present study was to evaluate the DNA methylation status of seven clock genes, namely clock, arntl, per1-3 and cry1-2, in a cohort of chronobiologically characterized obese adolescents (n: 45: F/M: 28/17; age ± SD: 15.8 ± 1.4 yrs; BMI SDS: 2.94 [2.76; 3.12]) hospitalized for a 3-week multidisciplinary body weight reduction program (BWRP), as well as a series of cardiometabolic outcomes and markers of hypothalamo-pituitary-adrenal (HPA) function. At the end of the intervention, an improvement in body composition was observed (decreases in BMI SDS and fat mass), as well as glucometabolic homeostasis (decreases in glucose, insulin, HOMA-IR and Hb1Ac), lipid profiling (decreases in total cholesterol, LDL-C, triglycerides and NEFA) and cardiovascular function (decreases in systolic and diastolic blood pressures and heart rate). Moreover, the BWRP reduced systemic inflammatory status (i.e., decrease in C-reactive protein) and HPA activity (i.e., decreases in plasma ACTH/cortisol and 24 h urinary-free cortisol excretion). Post-BWRP changes in the methylation levels of clock, cry2 and per2 genes occurred in the entire population, together with hypermethylation of clock and per3 genes in males and in subjects with metabolic syndrome. In contrast to the pre-BWRP data, at the end of the intervention, cardiometabolic parameters, such as fat mass, systolic and diastolic blood pressures, triglycerides and HDL-C, were associated with the methylation status of some clock genes. Finally, BWRP induced changes in clock genes that were associated with markers of HPA function. In conclusion, when administered to a chronodisrupted pediatric obese population, a short-term BWRP is capable of producing beneficial cardiometabolic effects, as well as an epigenetic remodeling of specific clock genes, suggesting the occurrence of a post-BWRP metabolic and endocrine chronoresynchronization, which might represent a "biomolecular" predictor of successful antiobesity intervention.
Subject(s)
Pediatric Obesity , Weight Reduction Programs , Male , Humans , Adolescent , Child , DNA Methylation , Pediatric Obesity/genetics , Weight Loss , Triglycerides , Endocrine SystemABSTRACT
Diet has long been known to influence the course of chronic kidney disease (CKD) and may even result in acute kidney injury (AKI). Diet may influence kidney disease through a direct impact of specific nutrients on the human body through modulation of the gut microbiota composition or through metabolites generated by the gut microbiota from ingested nutrients. The potential for interaction between diet, microbiota and CKD has fueled research into interventions aimed at modifying the microbiota to treat CKD. These interventions may include diet, probiotics, prebiotics, fecal microbiota transplant and other interventions that modulate the microbiota and its metabolome. A recent report identified Lactobacillus casei Zhang from traditional Chinese koumiss as a probiotic that may protect mice from AKI and CKD and slow CKD progression in humans. Potential mechanisms of action include modulation of the gut microbiota and increased availability of short-chain fatty acids with anti-inflammatory properties and of nicotinamide. However, the clinical relevance needs validation in large well-designed clinical trials.
ABSTRACT
Vascular smooth muscle cells (VSMCs) are key participants in both early- and late-stage atherosclerosis and influence neighbouring cells possibly by means of bioactive molecules, some of which are packed into extracellular vesicles (EVs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed and secreted by VSMCs. This study aimed to unravel the role of PCSK9 on VSMCs-derived EVs in terms of content and functionality. EVs were isolated from human VSMCs overexpressing human PCSK9 (VSMCPCSK9-EVs) and tested on endothelial cells, monocytes, macrophages and in a model of zebrafish embryos. Compared to EVs released from wild-type VSMCs, VSMCPCSK9-EVs caused a rise in the expression of adhesion molecules in endothelial cells and of pro-inflammatory cytokines in monocytes. These acquired an increased migratory capacity, a reduced oxidative phosphorylation and secreted proteins involved in immune response and immune effector processes. Concerning macrophages, VSMCPCSK9-EVs enhanced inflammatory milieu and uptake of oxidized low-density lipoproteins, whereas the migratory capacity was reduced. When injected into zebrafish embryos, VSMCPCSK9-EVs favoured the recruitment of macrophages toward the site of injection. The results of the present study provide evidence that PCSK9 plays an inflammatory role by means of EVs, at least by those derived from smooth muscle cells of vascular origin.
Subject(s)
Extracellular Vesicles , Proprotein Convertase 9 , Animals , Humans , Proprotein Convertase 9/metabolism , Muscle, Smooth, Vascular/metabolism , Zebrafish/metabolism , Endothelial Cells/metabolism , Myocytes, Smooth Muscle/metabolism , Extracellular Vesicles/metabolismABSTRACT
The possibility of characterizing the extracellular vesicles (EVs) based on parental cell surface markers and their content makes them a new attractive prognostic biomarker. Thus, our study aims to verify the role of EVs as relevant prognostic factors for acute and mid-term outcomes in ischemic stroke. Forty-seven patients with acute ischemic stroke were evaluated at admission (T0), immediately after recanalization treatment or after 2 h in non-treated patients (T1) and after one week (Tw) using the National Institutes of Health Stroke Scale (NIHSS), and after 3 months using the Modified Rankin Scale (mRS). Total count and characterization of EVs were assessed by Nanosight analysis and flow cytometry. The relationships between stroke outcomes and EV count were assessed through multivariable negative binomial regression models. We found that the amount of platelet-derived EVs at admission was positively associated with the severity of ischemic stroke at the onset as well as with the severity of mid-term outcome. Moreover, our study revealed that T-cell-derived EVs at admission were positively related to both early and mid-term ischemic stroke outcomes. Finally, T-cell-derived EVs at T1 were positively related to mid-term ischemic stroke outcome. The present study suggests that specific EV subtypes are associated with stroke severity and both short- and long-term outcomes. EVs could represent a valid tool to improve risk stratification in patients with ischemic stroke and post-recanalization treatment monitoring.
ABSTRACT
Air particulate matter (PM) exposure has been associated with increased cardiovascular risk, especially in obesity. By triggering inflammation and oxidative stress, PM could impact atheroprotection by high-density lipoproteins (HDL). The aim of the study was to assess the relationship between short-term exposure to PM and HDL function, and the modifying effect of body mass index (BMI). Daily exposures to PM10 and PM2.5 of 50 subjects with overweight/obesity and 41 healthy volunteers with BMI < 30 kg/m2 were obtained from fixed monitoring stations. HDL function was assessed as promotion of nitric oxide (NO) release by endothelial cells and reduction in cholesterol in macrophages. HDL-induced NO release progressively declined with the increase in BMI. No association was found between HDL function and PM exposure, but a modifying effect of BMI was observed. The positive association between PM10 exposure at day −1 and NO production found at normal BMI values was lost in participants with higher BMI. Similar results were obtained for the reduction in macrophage cholesterol. The loss of the compensatory response of HDL function to PM exposure at increasing BMI levels could contribute to the endothelial dysfunction induced by PM and help to explain the susceptibility of subjects with obesity to air pollution.
ABSTRACT
BACKGROUND: A few studies suggest that particulate matter (PM) exposure might play a role in bronchiolitis. However, available data are mostly focused on the risk of hospitalization and come from retrospective studies that provided conflicting results. This prospective study investigated the association between PM (PM2.5 and PM10 ) exposure and the severity of bronchiolitis. METHODS: This prospective cohort study was conducted between November 2019 and February 2020 at the pediatric emergency department of the Fondazione IRCCS Ca' Ospedale Maggiore Policlinico, Milan, Italy. Infants <1 year of age with bronchiolitis were eligible. The bronchiolitis severity score was assessed in each infant and a nasal swab was collected to detect respiratory viruses. The daily PM10 and PM2.5 exposure in the 29 preceding days were considered. Adjusted regression models were employed to evaluate the association between the severity score and PM10 and PM2.5 exposure. RESULTS: A positive association between the PM2.5 levels and the severity score was found at day-2 (ß 0.0214, 95% CI 0.0011-0.0417, p = .0386), day-5 (ß 0.0313, 95% CI 0.0054-0.0572, p = .0179), day-14 (ß 0.0284, 95% CI 0.0078-0.0490, p = .0069), day-15 (ß 0.0496, 95% CI 0.0242-0.0750, p = .0001) and day-16 (ß 0.0327, 95% CI 0.0080-0.0574, p = .0093).Similar figures were observed considering the PM10 exposure and limiting the analyses to infants with respiratory syncytial virus. CONCLUSION: This study shows for the first time a direct association between PM2.5 and PM10 levels and the severity of bronchiolitis.
Subject(s)
Air Pollutants , Air Pollution , Bronchiolitis , Infant , Child , Humans , Particulate Matter/adverse effects , Prospective Studies , Cohort Studies , Retrospective Studies , Bronchiolitis/epidemiology , Environmental Exposure , Air Pollutants/adverse effects , Air Pollutants/analysisABSTRACT
Chronic kidney disease (CKD) is projected to become the fifth global cause of death by 2040 as a result of key shortcomings in the current methods available to diagnose and treat kidney diseases. In this regard, the novel holobiont concept, used to describe an individual host and its microbial community, may pave the way towards a better understanding of kidney disease pathogenesis and progression. Microbiota-modulating or -derived interventions include probiotics, prebiotics, synbiotics and postbiotics. As of 2019, the concept of postbiotics was updated by the International Scientific Association of Probiotics and Prebiotics (ISAPP) to refer to preparations of inanimate microorganisms and/or their components that confer a health benefit to the host. By explicitly excluding purified metabolites without a cellular biomass, any literature making use of such term is potentially rendered obsolete. We now review the revised concept of postbiotics concerning their potential clinical applications and research in kidney disease, by discussing in detail several formulations that are undergoing preclinical development such as GABA-salt for diet-induced hypertension and kidney injury, sonicated Lactobacillus paracasei in high fat diet-induced kidney injury, GABA-salt, lacto-GABA-salt and postbiotic-GABA-salt in acute kidney injury, and O. formigenes lysates for hyperoxaluria. Furthermore, we provide a roadmap for postbiotics research in kidney disease to expedite clinical translation.
Subject(s)
Kidney Diseases , Probiotics , Synbiotics , Humans , Kidney Diseases/etiology , Kidney Diseases/therapy , Prebiotics , Probiotics/therapeutic use , gamma-Aminobutyric AcidABSTRACT
The "gold standard" method for detection of SARS-CoV-2 is the real time reverse transcription-polymerase chain reaction, but due to pre-analytical and technical limitations, biological samples with low viral load are not sometimes detected. For this purpose a digital RT-PCR method on-chip was developed for detection of the SARS-CoV-2 virus, using two TaqMan™ Assays for quantification of the N Protein (Nucleocapsid) and the S Protein (Spike), and the QuantStudio™ 3D Digital PCR instrument. The method was applied to assess the nasopharyngeal swabs of asymptomatic subjects recruited in the UNICORN Study. The digital RT-PCR method is characterized by a higher sensitivity than the RT-qPCR method, even if performed with the same TaqMan™, and could be a promising tool for SARS-CoV-2 viral load quantification.
Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnosis , COVID-19 Testing , Humans , RNA, Viral/analysis , RNA, Viral/genetics , Real-Time Polymerase Chain Reaction/methods , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , Sensitivity and SpecificityABSTRACT
Obesity and aging share common molecular and cellular mechanisms underlying the pathophysiology of cardiovascular diseases (CVD), which occur frequently in both conditions. DNA methylation (DNAm) age, a biomarker of the epigenetic clock, has been proposed as a more accurate predictor of biological aging than chronological age. A positive difference between an individual's chronological age and DNAm age is referred to as epigenetic age acceleration. The objective of the present study was to evaluate the effects of a 3-week in-hospital body weight reduction program (BWRP) on the epigenetic age acceleration, as well as on other cardiometabolic outcomes, in a cohort of 72 obese adults (F/M: 43/29; (chronological) age: 51.5 ± 14.5 yrs; BMI: 46.5 ± 6.3 kg/m2). At the end of the BWRP, when considering the entire population, BMI decreased, and changes in body composition were observed. The BWRP also produced beneficial metabolic effects as demonstrated by decreases in glucose, insulin, HOMA-IR, total cholesterol, and LDL cholesterol. A post-BWRP improvement in cardiovascular function was also evident (i.e., decreases in systolic and diastolic blood pressures and heart rate). The BWRP reduced some markers of systemic inflammation, particularly C-reactive protein (CRP). Finally, vascular age (VA) and Framingham risk score (FRS) were reduced after the BWRP. When considering the entire population, DNAm age and epigenetic age acceleration did not differ after the BWRP. However, when subdividing the population into two groups based on each subject's epigenetic age acceleration (i.e., ≤0 yrs or >0 yrs), the BWRP reduced the epigenetic age acceleration only in obese subjects with a value > 0 yrs (thus biologically older than expected). Among all the single demographic, lifestyle, biochemical, and clinical characteristics investigated, only some markers of systemic inflammation, such as CRP, were associated with the epigenetic age acceleration. Moreover, chronological age was correlated with DNAm age and VA; finally, there was a correlation between DNAm age and VA. In conclusion, a 3-week BWRP is capable of reducing the epigenetic age acceleration in obese adults, being the BWRP-induced rejuvenation evident in subjects with an epigenetic age acceleration > 0 yrs. Based on the BWRP-induced decrease in CRP levels, chronic systemic inflammation seems to play a role in mediating obesity-related epigenetic remodeling and biological aging. Thus, due to the strong association of CVD risk with the epigenetic clock and morbidity/mortality, any effort should be made to reduce the low-grade chronic inflammatory state in obesity.
ABSTRACT
Background: Obesity and depression are intertwined diseases often associated with an increased risk of cardiovascular (CV) complications. Brain-Derived Neurotrophic Factor (BDNF), altered in the brain both of subjects with depression and obesity, provides a potential link between depression and thrombosis. Since the relationship among peripheral BDNF, depression and obesity is not well-defined, the aim of the present report has been to address this issue taking advantage of the contribution played by extracellular vesicle (EV)-derived miRNAs. Research Process: Associations among circulating BDNF, depression and EV-derived miRNAs related to atherothrombosis have been evaluated in a large Italian cohort of obese individuals (n = 743), characterized by the Beck Depression Inventory (BDI-II) score. Results: BDI-II was negatively associated with BDNF levels without a significant impact of the rs6265 BDNF polymorphism; this association was modified by raised levels of IFN-γ. BDNF levels were linked to an increase of 80 EV-derived miRNAs and a decrease of 59 miRNAs related to atherosclerosis and thrombosis. Network analysis identified at least 18 genes targeted by these miRNAs, 7 of which involved in depression and CV risk. The observation of a possible link among BDNF, depression, and miRNAs related to atherothrombosis and depression in obesity is novel and may lead to a wider use of BDNF as a CV risk biomarker in this specific subject group.
ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), ranging from asymptomatic conditions to severe/fatal lung injury and multi-organ failure. Growing evidence shows that the nasopharyngeal microbiota composition may predict the severity of respiratory infections and may play a role in the protection from viral entry and the regulation of the immune response to the infection. In the present study, we have characterized the nasopharyngeal bacterial microbiota (BNM) composition and have performed factor analysis in a group of 54 asymptomatic/paucisymptomatic subjects who tested positive for nasopharyngeal swab SARS-CoV-2 RNA and/or showed anti-RBD-IgG positive serology at the enrolment. We investigated whether BNM was associated with SARS-CoV-2 RNA positivity and serum anti-RBD-IgG antibody development/maintenance 20-28 weeks after the enrolment. Shannon's entropy α-diversity index [odds ratio (OR) = 5.75, p = 0.0107] and the BNM Factor1 (OR = 2.64, p = 0.0370) were positively associated with serum anti-RBD-IgG antibody maintenance. The present results suggest that BNM composition may influence the immunological memory against SARS-CoV-2 infections. To the best of our knowledge, this is the first study investigating the link between BNM and specific IgG antibody maintenance. Further studies are needed to unveil the mechanisms through which the BNM influences the adaptive immune response against viral infections.
Subject(s)
COVID-19 , Microbiota , Antibodies, Viral , Humans , Immunoglobulin G , Nasopharynx , RNA, Viral/genetics , SARS-CoV-2ABSTRACT
Maternal obesity is associated with inflammation and oxidative stress, strongly impacting the intrauterine environment with detrimental consequences for both mother and offspring. The saliva is a non-invasive biofluid reflecting both local and systemic health status. This observational study aimed to profile the epigenetic signature in the saliva of Obese (OB) and Normal-Weight (NW) pregnant women. Sixteen NW and sixteen OB Caucasian women with singleton spontaneous pregnancies were enrolled. microRNAs were quantified by the OpenArray Platform. The promoter region methylation of Suppressor of Cytokine Signaling 3 (SOCS3) and Transforming Growth Factor Beta 1 (TGF-Beta1) was assessed by pyrosequencing. There were 754 microRNAs evaluated: 20 microRNAs resulted in being differentially expressed between OB and NW. microRNA pathway enrichment analysis showed a significant association with the TGF-Beta signaling pathway (miTALOS) and with fatty acids biosynthesis/metabolism, lysine degradation, and ECM-receptor interaction pathways (DIANA-miRPath). Both SOCS3 and TGF-Beta1 were significantly down-methylated in OB vs. NW. These results help to clarify impaired mechanisms involved in obesity and pave the way for the understanding of specific damaged pathways. The characterization of the epigenetic profile in saliva of pregnant women can represent a promising tool for the identification of obesity-related altered mechanisms and of possible biomarkers for early diagnosis and treatment of pregnancy-adverse conditions.
Subject(s)
Epigenesis, Genetic , MicroRNAs , Obesity , Pregnancy Complications , DNA Methylation , Female , Humans , MicroRNAs/genetics , Obesity/genetics , Pregnancy , Pregnancy Complications/genetics , Pregnant Women , Promoter Regions, Genetic , Saliva/metabolism , Suppressor of Cytokine Signaling 3 Protein/genetics , Transforming Growth Factor beta1/geneticsABSTRACT
OBJECTIVE: To evaluate whether telomere length (TL), mitochondrial-DNA (mt-DNA) or epigenetic age estimators based on DNA methylation (DNAm) pattern could be considered reliable predictors of in-vitro-fertilization (IVF) success in terms of live birth rate. DESIGN: Prospective cohort study. SETTING: Infertility Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. PATIENTS: 181 women aged 37-39 years who underwent IVF at a single-centre between January 2017 and December 2018. INTERVENTIONS: On the day of recruitment, blood samples were collected, and genomic DNA was isolated from white blood cells. TL, mt-DNA and DNAm assessment was performed using quantitative real-time polymerase chain reaction (qPCR). Biological age (DNAm age) was computed as the algorithm based on methylation pattern of five genes. Epigenetic age acceleration was estimated from the residuals of the linear model of epigenetic age regressed on chronological age. Long Interspersed Nuclear Elements (LINE)-1 methylation pattern was used as a surrogate for global DNA methylation. MAIN OUTCOME MEASURES: This study investigated whether peripheral TL, mt-DNA and DNAm could predict live birth in IVF cycles. RESULTS: TL, mt-DNA and LINE-1 methylation were not associated with IVF success. Conversely, DNAm age resulted significantly lower in women who had a live birth compared to women who did not (36.1 ± 4.2 and 37.3 ± 3.3 years, respectively, p = 0.04). For DNAm age, odds ratio (OR) for live birth per year of age was 0.90 (95%CI: 0.82-0.99, p = 0.036) after adjusting for FSH and antral follicle count (AFC) and 0.90 (95%CI: 0.82-0.99, p = 0.028) after adjusting also for number of oocytes retrieved. A significant association also emerged for epigenetic age acceleration after adjustments (OR = 0.91, 95%CI: 0.83-1.00, p = 0.048). CONCLUSION: DNAm age is associated with IVF success but the magnitude of this association is insufficient to claim a clinical use. However, our findings are promising and warrant further investigation. Assessment of biological age using different epigenetic clocks or focusing on different tissues may reveal new predictors of IVF success.
Subject(s)
DNA Methylation , DNA, Mitochondrial/genetics , Mitochondria/genetics , Telomere Homeostasis , Adult , Birth Rate , Epigenesis, Genetic , Female , Fertilization in Vitro , Humans , Italy , Long Interspersed Nucleotide Elements , Maternal Age , Pregnancy , Pregnancy Rate , Prospective StudiesABSTRACT
Introduction: Night shift (NS) work has been associated with an increased risk of different conditions characterized by altered inflammatory and immune responses, such as cardio-metabolic and infectious diseases, cancer, and obesity. Epigenetic modifications, such as DNA methylation, might mirror alterations in biological processes that are influenced by NS work. Methods: The present study was conducted on 94 healthy female workers with different working schedules and aimed at identifying whether NS was associated with plasmatic concentrations of the inflammatory proteins NLRP3 and TNF-alpha, as well as with DNA methylation levels of ten human endogenous retroviral (HERV) sequences, and nine genes selected for their role in immune and inflammatory processes. We also explored the possible role of the body mass index (BMI) as an additional susceptibility factor that might influence the effects of NS work on the tested epigenetic modifications. Results and discussion: We observed a positive association between NS and NLRP3 levels (p-value 0.0379). Moreover, NS workers retained different methylation levels for ERVFRD-1 (p-value = 0.0274), HERV-L (p-value = 0.0377), and HERV-P (p-value = 0.0140) elements, and for BIRC2 (p-value = 0.0460), FLRT3 (p-value = 0.0422), MIG6 (p-value = 0.0085), and SIRT1 (p-value = 0.0497) genes. We also observed that the BMI modified the relationship between NS and the methylation of ERVE, HERV-L, and ERVW-1 elements. Overall, our results suggest that HERV methylation could pose as a promising biomolecular sensor to monitor not only the effect of NS work but also the cumulative effect of multiple stressors.