Circulating miRNAs as Biomarkers of Obesity and Obesity-Associated Comorbidities in Children and Adolescents: A Systematic Review

Early detection of obesity and its associated comorbidities in children needs priority for the development of effective therapeutic intervention. Circulating miRNAs (microRNAs) have been proposed as biomarkers for obesity and its comorbidities; therefore, we conducted a systematic review to summarize results of studies that have quantified the profile of miRNAs in children and adolescents with obesity and/or associated disorders. Nine studies aiming to examine differences in miRNA expression levels between children with normal weight and obesity or between obese children with or without cardiometabolic diseases were included in this review. We identified four miRNAs overexpressed in obesity (miR-222, miR-142–3, miR-140-5p, and miR-143) and two miRNAs (miR-122 and miR-34a) overexpressed in children with obesity and nonalcoholic fatty liver disease (NAFLD) and/or insulin resistance. In conclusion, circulating miRNAs are promising diagnostic biomarkers of obesity-associated diseases such as NAFLD and type 2 diabetes already in childhood. However, more studies in children, using massive search technology and with larger sample sizes, are required to draw any firm conclusions.This research was funded by the Spanish Ministry of Industry and Competitiveness (DEP2016-78377-R) and by the European Regional Development Fund (ERDF), M.O. is supported by a grant from the Spanish Ministry of Economy and Competitiveness, grant number; BES-2017-080770 and the APC was funded by additional support from the University of Granada, UGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions Programme, and Excellence Actions Programe. C.M.A. and I.L.G. are part of the “URG Plan propio de Investigación 2016” and the “Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada

LC-IMS-HRMS for identification of biomarkers in untargeted metabolomics: The effects of pterostilbene and resveratrol consumption in liver steatosis, animal model

Untargeted metabolomics with the combination of ion mobility separation coupled to high resolution mass spectrometry (IMS-HRMS) was applied to investigate the impact of resveratrol and pterostilbene supplementation on the metabolic fingerprint of the Wistar rats liver with induced liver steatosis. RP-LC and HILIC in both ionisation modes were employed to analyse the liver samples (n = 40) from Wistar rats fed with a high-fat and high-fructose diet, supplemented or not with resveratrol and pterostilbene. After univariate and multivariate statistical analysis, 34 metabolites were highlighted in the different diets and elucidated. Despite the structural similarity, different alterations in liver metabolism were observed by the supplementations. Resveratrol treatment was characterised by the alteration in metabolism of 17 lysophospholipids, while pterostilbene affected some vitamins and derivatives, among others. IMS has demonstrated great potential in the elucidation process thanks to the additional structural descriptor the CCS (Å2), providing more confidence in the identification

Effects of the whole seed and a protein isolate of faba bean (Vicia faba) on the cholesterol metabolism of hypercholesterolaemic rats

The aim of the present work was to analyse the hypocholesterolaemic efficiency of a Vicia fabaprotein isolate in relation to the intact legume. In addition, the mechanisms underlying the effects of this isolate were investigated. Hypercholesterolaemic rats were divided into three groups n10 3 and fed high-fat diets rich in cholesterol-containing casein, whole seeds of Vicia faba or the protein isolate of faba beans as protein source, for 2 weeks ad libitum. The protein isolate was prepared by isoelectric precipitation and spray dried. Analyses of serum, liver and faeces, as well as of the activity of hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, were assessed by enzymatic methods. The rats fed on Vicia faba diets showed significantly lower body weights and energy intakes than rats fed on casein diets. The wholeseed diet induced a significant reduction in plasma triacylglycerol. Feeding rats on diets containing faba bean seeds, or the protein isolate, induced a significant decrease in plasma (LDL+VLDL)-cholesterol but not in HDL-cholesterol. Hepatic cholesterol and triacylglycerol were also reduced. The hypocholesterolaemic effects of Vicia faba were not the result of a reduction in cholesterol synthesis as assessed from HMG-CoA reductase activity, but the result of an increase in steroid faecal excretion. The faba bean-protein isolate obtained under our experimental conditions was useful in improving the metabolic alterations induced by feeding with a hypercholesterolaemic diet compared with casein. The effectiveness of the whole seeds was higher than that of the protein isolate

Inter-Individual variability in insulin response after grape pomace supplementation in subjects at high cardiometabolic risk: role of microbiota and miRNA

Scope Dietary polyphenols have shown promising effects in mechanistic and preclinical studies on the regulation of cardiometabolic alterations. Nevertheless, clinical trials have provided contradictory results, with high inter‐individual variability. This study explores the role of gut microbiota and microRNAs (miRNAs) as factors contributing to the inter‐individual variability in polyphenol response. Methods and Results 49 subjects with at least two factors of metabolic syndrome are divided between responders (n = 23) or non‐responders (n = 26), depending on the variation rate in fasting insulin after grape pomace supplementation (6 weeks). The populations of selected fecal bacteria are estimated from fecal deoxyribonucleic acid (DNA) by quantitative real‐time polymerase chain reaction (qPCR), while the microbial‐derived short‐chain fatty acids (SCFAs) are measured in fecal samples by gas chromatography. MicroRNAs are analyzed on a representative sample, followed by targeted miRNA analysis. Responder subjects show significantly lower (p < 0.05) Prevotella and Firmicutes levels, and increased (p < 0.05) miR‐222 levels. Conclusion After evaluating the selected substrates for Prevotella and target genes of miR‐222, these variations suggest that responders are those subjects exhibiting impaired glycaemic control. This study shows that fecal microbiota and miRNA expression may be related to inter‐individual variability in clinical trials with polyphenols

Epigenetic Landscape in Blood Leukocytes Following Ketosis and Weight Loss Induced by a Very Low Calorie Ketogenic Diet (VLCKD) in Patients With Obesity

[Abstract] Background:The molecular mechanisms underlying the potential health benefits of a ketogenic diet areunknown and could be mediated by epigenetic mechanisms.Objective:To identify the changes in the obesity-related methylome that are mediated by the inducedweight loss or are dependent on ketosis in subjects with obesity underwent a very-low calorie ketogenicdiet (VLCKD).Methods:Twenty-one patients with obesity (n¼12 women, 47.9±1.02 yr, 33.0±0.2 kg/m2) after 6months on a VLCKD and 12 normal weight volunteers (n¼6 women, 50.3±6.2 yrs, 22.7±1.5 kg/m2)were studied. Data from the Infinium MethylationEPIC BeadChip methylomes of blood leukocytes wereobtained at time points of ketotic phases (basal, maximum ketosis, and out of ketosis) during VLCKD(n¼10) and at baseline in volunteers (n¼12). Results were further validated by pyrosequencing inrepresentative cohort of patients on a VLCKD (n¼18) and correlated with gene expression.Results:After weight reduction by VLCKD, differences were found at 988 CpG sites (786 unique genes).The VLCKD altered methylation levels in patients with obesity had high resemblance with those fromnormal weight volunteers and was concomitant with a downregulation of DNA methyltransferases(DNMT)1, 3a and 3b. Most of the encoded genes were involved in metabolic processes, protein meta-bolism, and muscle, organ, and skeletal system development. Novel genes representing the top scoringassociated events were identified, includingZNF331,FGFRL1(VLCKD-induced weight loss) andCBFA2T3,C3orf38,JSRP1, andLRFN4(VLCKD-induced ketosis). Interestingly,ZNF331andFGFRL1were validated inan independent cohort and inversely correlated with gene expression.Conclusions:The beneficial effects of VLCKD therapy on obesity involve a methylome more suggestive ofnormal weight that could be mainly mediated by the VLCKD-induced ketosis rather than weight loss.This work was supported by the PronoKal Group® and grants from the Fondo de Investigacion Sanitaria as well as PI17/01287, PI20/00628 and PI20/00650 research projects and CIBERobn from the Instituto de Salud Carlos III (ISCIII)-Subdireccion General de Evaluacion y Fomento de la Investigación; Fondo Europeo de Desarrollo Regional (FEDER) Ana B Crujeiras is funded by a research contract “Miguel Servet” (CP17/00088) from the ISCIII, co-financed by the European Regional Development Fund (FEDER) and Xunta de Galicia-GAIN (IN607B2020)Xunta de Galicia; IN607B202

Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas

Basal-like breast carcinoma is characterized by the expression of basal/ myoepithelial markers, undifferentiated phenotype, highly aggressive behaviour and frequent triple negative status (ESR , PR , Her2neu ). We have previously shown that epithelial–mesenchymal transition (EMT) occurs in basal-like breast tumours and identified Lysyl-oxidase-like 2 (LOXL2) as an EMT player and poor prognosis marker in squamous cell carcinomas. We now show that LOXL2 mRNA is overexpressed in basal-like human breast carcinomas. Breast carcinoma cell lines with basal-like phenotype show a specific cytoplasmic/perinuclear LOXL2 expression, and this subcellular distribution is significantly associated with distant metastatic incidence in basal-like breast carcinomas. LOXL2 silencing in basal-like carcinoma cells induces a mesenchymal-epithelial transition (MET) associated with a decrease of tumourigenicity and suppression of metastatic potential. Mechanistic studies indicate that LOXL2 maintains the mesenchymal phenotype of basal-like carcinoma cells by a novel mechanism involving transcriptional downregulation of Lgl2 and claudin1 and disorganization of cell polarity and tight junction complexes. Therefore, intracellular LOXL2 is a new candidate marker of basal-like carcinomas and a target to block metastatic dissemination of this aggressive breast tumour subtypeThis work was supported by grants from the Spanish Ministry of Science and Innovation, MICINN, (SAF2007-53061; SAF2010-21143; Consolider Ingenio CSD2007/00017, to AC; SAF2007-63075; SAF2010-20175 to GM-B); Fundacion Mutua Madrileña (2007, 2009 to AC and GM-B); Instituto de Salud Carlos III (ISCIII) (PI 080971 to JP), and Junta de Andalucıa (PI-0384/2007; PI 080971, P07-CVI- 03100 to JP). FS and A Martı´n are recipients of JAE-pre and JAE-postdoc contracts from the Spanish Research Council (CSIC), respectively; MAC is founded by the RETICS (ISCIII)

Morphological and Transcriptional Changes in Human Bone Marrow During Natural Plasmodium vivax Malaria Infections.

--- - Label: BACKGROUND NlmCategory: BACKGROUND content: The presence of Plasmodium vivax malaria parasites in the human bone marrow (BM) is still controversial. However, recent data from a clinical case and experimental infections in splenectomized nonhuman primates unequivocally demonstrated the presence of parasites in this tissue. - Label: METHODS NlmCategory: METHODS content: In the current study, we analyzed BM aspirates of 7 patients during the acute attack and 42 days after drug treatment. RNA extracted from CD71+ cell suspensions was used for sequencing and transcriptomic analysis. - Label: RESULTS NlmCategory: RESULTS content: We demonstrated the presence of parasites in all patients during acute infections. To provide further insights, we purified CD71+ BM cells and demonstrated dyserythropoiesis and inefficient erythropoiesis in all patients. In addition, RNA sequencing from 3 patients showed that genes related to erythroid maturation were down-regulated during acute infections, whereas immune response genes were up-regulated. - Label: CONCLUSIONS NlmCategory: CONCLUSIONS content: This study thus shows that during P. vivax infections, parasites are always present in the BM and that such infections induced dyserythropoiesis and ineffective erythropoiesis. Moreover, infections induce transcriptional changes associated with such altered erythropoietic response, thus highlighting the importance of this hidden niche during natural infections

Engagement with Care, Substance Use, and Adherence to Therapy in HIV/AIDS

Engagement with care for those living with HIV is aimed at establishing a strong relationship between patients and their health care provider and is often associated with greater adherence to therapy and treatment (Flickinger, Saha, Moore, and Beach, 2013). Substance use behaviors are linked with lower rates of engagement with care and medication adherence (Horvath, Carrico, Simoni, Boyer, Amico, and Petroli, 2013). This study is a secondary data analysis using a cross-sectional design from a larger randomized controlled trial (n = 775) that investigated the efficacy of a self-care symptom management manual for participants living with HIV. Participants were recruited from countries of Africa and the US. This study provides evidence that substance use is linked with lower self-reported engagement with care and adherence to therapy. Data on substance use and engagement are presented. Clinical implications of the study address the importance of utilizing health care system and policy factors to improve engagement with care