|
1
|
Mukherjee S, Im SS. Decoding Health: Exploring Essential Biomarkers Linked to Metabolic Dysfunction-Associated Steatohepatitis and Type 2 Diabetes Mellitus. Biomedicines 2025; 13:359. [PMID: 40002771 PMCID: PMC11853123 DOI: 10.3390/biomedicines13020359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 01/24/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
The investigation of biomarkers for metabolic diseases such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatohepatitis (MASH) reveals their potential for advancing disease treatment and addressing their notable overlap. The connection between MASH, obesity, and T2DM highlights the need for an integrative management approach addressing mechanisms like insulin resistance and chronic inflammation. Obesity contributes significantly to the development of MASH through lipid dysregulation, insulin resistance, and chronic inflammation. Selective biomarker targeting offers a valuable strategy for detecting these comorbidities. Biomarkers such as CRP, IL-6, and TNF-α serve as indicators of inflammation, while HOMA-IR, fasting insulin, and HbA1c are essential for evaluating insulin resistance. Additionally, triglycerides, LDL, and HDL are crucial for comprehending lipid dysregulation. Despite the growing importance of digital biomarkers, challenges in research methodologies and sample variability persist, necessitating further studies to validate diagnostic tools and improve health interventions. Future opportunities include developing non-invasive biomarker panels, using multiomics, and using machine learning to enhance prognoses for diagnostic accuracy and therapeutic outcomes.
Collapse
Affiliation(s)
| | - Seung-Soon Im
- Department of Physiology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea
| |
Collapse
|
|
2
|
Mansour RM, Abdel Mageed SS, Abulsoud AI, Sayed GA, Lutfy RH, Awad FA, Sadek MM, Shaker AAS, Mohammed OA, Abdel-Reheim MA, Elimam H, Doghish AS. From fatty liver to fibrosis: the impact of miRNAs on NAFLD and NASH. Funct Integr Genomics 2025; 25:30. [PMID: 39888504 DOI: 10.1007/s10142-025-01544-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/30/2024] [Accepted: 01/27/2025] [Indexed: 02/01/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease with various levels varying from fatty liver steatosis to acute steatosis which is non-alcoholic steatohepatitis (NASH), which can develop into hepatic failure, as well as in some conditions it can develop into hepatocellular carcinoma (HCC). In the NAFLD and NASH context, aberrant microRNA (miRNA) expression has a thorough contribution to the incidence and development of these liver disorders by influencing key biological actions, involving lipid metabolism, inflammation, and fibrosis. Dysregulated miRNAs can disrupt the balance between lipid accumulation and clearance, exacerbate inflammatory responses, and promote fibrogenesis, thus advancing the severeness of the disorder from simple steatosis to more complex NASH. In the current review, the latest development concerned with the activity of complex regulatory networks of miRNA in the incidence as well as the evolution of NAFLD is to be discussed, also conferring about the miRNAs' role in the onset, pathogenesis as well as diagnosis of NAFLD and NASH discussing miRNAs' role as diagnostic biomarkers and their therapeutic effects on NAFLD/NASH.
Collapse
Affiliation(s)
- Reda M Mansour
- Zoology and Entomology Department, Faculty of Science, Helwan University, Helwan, 11795, Egypt
- Biology Department, School of Biotechnology, Badr University in Cairo, Badr City, 11829, Cairo, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, 11785, Egypt
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Ghadir A Sayed
- Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt
| | - Radwa H Lutfy
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Farah A Awad
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Mohamed M Sadek
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Abanoub A S Shaker
- School of Biotechnology, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia
| | | | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, 11829, Cairo, Egypt.
- Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
| |
Collapse
|
|
3
|
Vijay B, Devkumar P, Saha G, RamachandraRao SP. Urine exosome biomarkers of obesity after Lekhana Basti treatment - Report of a pilot study. J Ayurveda Integr Med 2025; 16:101043. [PMID: 39879695 PMCID: PMC11803157 DOI: 10.1016/j.jaim.2024.101043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 07/09/2024] [Accepted: 07/24/2024] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND Obesity is a rising risk factor for various diseases including cardiovascular diseases and Cancer. The limitations of targeted obesity-treatment approaches employed in the clinic presently underscore the importance of developing integrative management strategies for identification of specific biomarkers of obesity. OBJECTIVES Given the specificity of exosome/extracellular vesicle (EV) biomarkers, we aimed here to identify the EV biomarkers of Ayurveda treatment - Lekhana Basti - for Obesity. METHODOLOGY A total of eighteen 24-h urine samples from 6 participants with BMI>30 kg/m2 were used in this study, collected over 3 time-points during the Lekhana basti (medicated enema for obesity) treatment. Urine EV were isolated using Polyethylene Glycol (PEG). The proteins were resolved by 1-d gel electrophoresis and identified using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and quantified by label-free methods. Significant Protein-Protein Interactions, KEGG pathway analysis and enrichment, functional gene ontology (GO) annotation were identified and shortlisted in comparison to Obesity reference genes from DisGeNET. RESULTS With UniProt as a reference subsequent to LC-MS/MS-identification, a total of 210 exosome proteins were identified. Seventy-three proteins were overexpressed in pathway enrichment analysis. Further, GO functional annotation identified 15 common proteins involved. Finally, the 8 hub proteins associated with obesity were identified and their differential expression profile compared between three different time-points during Lekhana Basti treatment. Six protein markers overexpressed during obesity were downregulated post Lekhana Basti treatment, while 2 markers increased in abundance post-treatment. CONCLUSION To our knowledge, this is the first study to isolate and identify urine EV protein abundance profiles from obese female participants of India. The study results indicate significant changes in the differential expression profile of 8 hub proteins involved in obesity, after Lekhana Basti treatment. The biomarker signature of the pilot study indicates the role of Ayurveda treatment and the possible pathways involved in the treatment of Obesity. Further, this study underlines the specificity of urine exosomes/EV as diagnostic markers as well as the potential of Ayurveda treatment in effective management of obesity.
Collapse
Affiliation(s)
- Bhavya Vijay
- Center for Clinical Research and Education, The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, India
| | - Poornima Devkumar
- Center for Clinical Research and Education, The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, India
| | - Gargi Saha
- Center for Clinical Research and Education, The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, India
| | - Satish P RamachandraRao
- Center for Clinical Research and Education, The University of Trans-Disciplinary Health Sciences and Technology, Bangalore, India; Internal Medicine - Cardiology, University of Michigan, Ann Arbor, MI, USA.
| |
Collapse
|
|
4
|
Zhu Q, Fu J, Hong L, Liu L, Yang S. Dysregulation of miR-21-5p in children with obesity and its predictive value for metabolic syndrome. Obes Res Clin Pract 2024; 18:436-442. [PMID: 39730292 DOI: 10.1016/j.orcp.2024.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 12/16/2024] [Accepted: 12/19/2024] [Indexed: 12/29/2024]
Abstract
BACKGROUND microRNAs (miRNAs) could mediate the glucose and lipid metabolism progress in metabolic syndrome (MetS). OBJECTIVES To analyze the value of miRNA (miR)-21-5p for MetS diagnosis in children with obesity. Function of miR-21-5p has been explored by the prediction of target genes and functional and pathway enrichment analysis. METHODS Relative miR-21-5p level was examined by qRT-PCR. Predictive value of miR-21-5p for MetS was assessed by ROC curve. miRBase, TargetScan, and miRWalk databases were used to screen the target genes of miR-21-5p. GO and KEGG were operated to analyze the function of candidate genes of miR-21-5p. RESULTS Overexpressed miR-21-5p was discovered in MetS children (P < 0.001). High miR-21-5p level could predict MetS patients from children with obesity. Serum miR-21-5p level was closely related to BMI (r = 0.631, P < 0.001), FBG (r = 0.341, P < 0.001), Fasting Insulin (r = 0.438, P < 0.001), TG (r = 0.662, P < 0.001), SBP (r = 0.432, P < 0.001), DBP (r = 0.524, P < 0.001), and HDL-C (r = -0.201, P < 0.001). High miR-21-5p level could predict MetS patients from children with obesity (AUC= 0.827, sensitivity= 0.750, specificity=0.806, cutoff value= 1.0293, P < 0.001). Venn diagram found 83 intersection genes among 3 databases. GO and KEGG analyses indicated that candidate genes of miR-21-5p were mainly correlated with Axon guidance, FoxO signaling pathway, cytokine-cytokine receptor interaction, and insulin resistance pathways. CONCLUSION Blood miR-21-5p was elevated in MetS children, and could predict MetS subjects from children with obesity. miR-21-5p could regulate the MetS development via FoxO signaling pathway and insulin resistance pathways.
Collapse
Affiliation(s)
- Qiuping Zhu
- Department of Pediatric, The Second Hospital of Jiaxing, Jiaxing 314000, China
| | - Jiayao Fu
- The First Clinical Medical School, Shanxi Medical University, Taiyuan 030001, China
| | - Li Hong
- Department of Laboratory, Haikou Hospital of The Maternal and Child Health, Haikou 570102, China
| | - Li Liu
- Department of General Practice, Affiliated Hospital of Panzhihua University, Panzhihua 617200, China.
| | - Shiyu Yang
- Department of General Practice, Geriatric Hospital Affiliated To Wuhan University of Science and Technology, Wuhan 433000, China.
| |
Collapse
|
|
5
|
Capetini VC, Quintanilha BJ, Garcia BREV, Rogero MM. Dietary modulation of microRNAs in insulin resistance and type 2 diabetes. J Nutr Biochem 2024; 133:109714. [PMID: 39097171 DOI: 10.1016/j.jnutbio.2024.109714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 07/13/2024] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
The prevalence of type 2 diabetes is increasing worldwide. Various molecular mechanisms have been proposed to interfere with the insulin signaling pathway. Recent advances in proteomics and genomics indicate that one such mechanism involves the post-transcriptional regulation of insulin signaling by microRNA (miRNA). These noncoding RNAs typically induce messenger RNA (mRNA) degradation or translational repression by interacting with the 3' untranslated region (3'UTR) of target mRNA. Dietary components and patterns, which can either enhance or impair the insulin signaling pathway, have been found to regulate miRNA expression in both in vitro and in vivo studies. This review provides an overview of the current knowledge of how dietary components influence the expression of miRNAs related to the control of the insulin signaling pathway and discusses the potential application of these findings in precision nutrition.
Collapse
Affiliation(s)
- Vinícius Cooper Capetini
- Nutritional Genomics and Inflammation Laboratory (GENUIN), Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil; Food Research Center (FoRC), São Paulo Research Foundation (FAPESP), São Paulo, Brazil; Faculty of Life Sciences and Medicine, School of Cancer and Pharmaceutical Sciences, Institute of Pharmaceutical Science, Department of Pharmacology, King's College London, London, United Kingdom.
| | - Bruna Jardim Quintanilha
- Nutritional Genomics and Inflammation Laboratory (GENUIN), Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil; Food Research Center (FoRC), São Paulo Research Foundation (FAPESP), São Paulo, Brazil
| | - Bruna Ruschel Ewald Vega Garcia
- Nutritional Genomics and Inflammation Laboratory (GENUIN), Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil
| | - Marcelo Macedo Rogero
- Nutritional Genomics and Inflammation Laboratory (GENUIN), Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil; Food Research Center (FoRC), São Paulo Research Foundation (FAPESP), São Paulo, Brazil
| |
Collapse
|
|
6
|
Colaianni F, Zelli V, Compagnoni C, Miscione MS, Rossi M, Vecchiotti D, Di Padova M, Alesse E, Zazzeroni F, Tessitore A. Role of Circulating microRNAs in Liver Disease and HCC: Focus on miR-122. Genes (Basel) 2024; 15:1313. [PMID: 39457437 PMCID: PMC11507253 DOI: 10.3390/genes15101313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 10/08/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
miR-122 is the most abundant microRNA (miRNA) in the liver; it regulates several genes mainly involved in cell metabolism and inflammation. Host factors, diet, metabolic disorders and viral infection promote the development of liver diseases, including hepatocellular carcinoma (HCC). The downregulation of miR-122 in tissue is a common feature of the progression of liver injury. In addition, the release of miR-122 in the bloodstream seems to be very promising for the early diagnosis of both viral and non-viral liver disease. Although controversial data are available on the role of circulating miR-122 as a single biomarker, high diagnostic accuracy has been observed using miR-122 in combination with other circulating miRNAs and/or proteins. This review is focused on comprehensively summarizing the most recent literature on the potential role of circulating miR-122, and related molecules, as biomarker(s) of metabolic liver diseases, hepatitis and HCC.
Collapse
Affiliation(s)
| | - Veronica Zelli
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy; (F.C.); (C.C.); (M.S.M.); (M.R.); (D.V.); (M.D.P.); (E.A.); (F.Z.); (A.T.)
| | | | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Fuller RN, Morcos A, Bustillos JG, Molina DC, Wall NR. Small non-coding RNAs and pancreatic ductal adenocarcinoma: Linking diagnosis, pathogenesis, drug resistance, and therapeutic potential. Biochim Biophys Acta Rev Cancer 2024; 1879:189153. [PMID: 38986720 DOI: 10.1016/j.bbcan.2024.189153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 07/03/2024] [Accepted: 07/05/2024] [Indexed: 07/12/2024]
Abstract
This review comprehensively investigates the intricate interplay between small non-coding RNAs (sncRNAs) and pancreatic ductal adenocarcinoma (PDAC), a devastating malignancy with limited therapeutic options. Our analysis reveals the pivotal roles of sncRNAs in various facets of PDAC biology, spanning diagnosis, pathogenesis, drug resistance, and therapeutic strategies. sncRNAs have emerged as promising biomarkers for PDAC, demonstrating distinct expression profiles in diseased tissues. sncRNA differential expression patterns, often detectable in bodily fluids, hold potential for early and minimally invasive diagnostic approaches. Furthermore, sncRNAs exhibit intricate involvement in PDAC pathogenesis, regulating critical cellular processes such as proliferation, apoptosis, and metastasis. Additionally, mechanistic insights into sncRNA-mediated pathogenic pathways illuminate novel therapeutic targets and interventions. A significant focus of this review is dedicated to unraveling sncRNA mechanisms underlying drug resistance in PDAC. Understanding these mechanisms at the molecular level is imperative for devising strategies to overcome drug resistance. Exploring the therapeutic landscape, we discuss the potential of sncRNAs as therapeutic agents themselves as their ability to modulate gene expression with high specificity renders them attractive candidates for targeted therapy. In summary, this review integrates current knowledge on sncRNAs in PDAC, offering a holistic perspective on their diagnostic, pathogenic, and therapeutic relevance. By elucidating the roles of sncRNAs in PDAC biology, this review provides valuable insights for the development of novel diagnostic tools and targeted therapeutic approaches, crucial for improving the prognosis of PDAC patients.
Collapse
Affiliation(s)
- Ryan N Fuller
- Department of Basic Science, Division of Biochemistry, Center for Health Disparity and Mol. Med., Loma Linda University, Loma Linda, CA 92350, USA; Department of Radiation Medicine, James M. Slater, MD Proton Treatment and Research Center, Loma Linda University, Loma Linda, CA 92350, USA
| | - Ann Morcos
- Department of Basic Science, Division of Biochemistry, Center for Health Disparity and Mol. Med., Loma Linda University, Loma Linda, CA 92350, USA; Department of Radiation Medicine, James M. Slater, MD Proton Treatment and Research Center, Loma Linda University, Loma Linda, CA 92350, USA
| | - Joab Galvan Bustillos
- Department of Basic Science, Division of Biochemistry, Center for Health Disparity and Mol. Med., Loma Linda University, Loma Linda, CA 92350, USA; Division of Surgical Oncology, Department of Surgery, Loma Linda University, Loma Linda, CA 92350, USA
| | - David Caba Molina
- Division of Surgical Oncology, Department of Surgery, Loma Linda University, Loma Linda, CA 92350, USA
| | - Nathan R Wall
- Department of Basic Science, Division of Biochemistry, Center for Health Disparity and Mol. Med., Loma Linda University, Loma Linda, CA 92350, USA; Department of Radiation Medicine, James M. Slater, MD Proton Treatment and Research Center, Loma Linda University, Loma Linda, CA 92350, USA.
| |
Collapse
|
|
8
|
Bizerea-Moga TO, Pitulice L, Bizerea-Spiridon O, Moga TV. Exploring the Link between Oxidative Stress, Selenium Levels, and Obesity in Youth. Int J Mol Sci 2024; 25:7276. [PMID: 39000383 PMCID: PMC11242909 DOI: 10.3390/ijms25137276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/16/2024] Open
Abstract
Obesity is a worldwide increasing concern. Although in adults this is easily estimated with the body mass index, in children, who are constantly growing and whose bodies are changing, the reference points to assess weight status are age and gender, and need corroboration with complementary data, making their quantification highly difficult. The present review explores the interaction spectrum of oxidative stress, selenium status, and obesity in children and adolescents. Any factor related to oxidative stress that triggers obesity and, conversely, obesity that induces oxidative stress are part of a vicious circle, a complex chain of mechanisms that derive from each other and reinforce each other with serious health consequences. Selenium and its compounds exhibit key antioxidant activity and also have a significant role in the nutritional evaluation of obese children. The balance of selenium intake, retention, and metabolism emerges as a vital aspect of health, reflecting the complex interactions between diet, oxidative stress, and obesity. Understanding whether selenium status is a contributor to or a consequence of obesity could inform nutritional interventions and public health strategies aimed at preventing and managing obesity from an early age.
Collapse
Affiliation(s)
- Teofana Otilia Bizerea-Moga
- Department XI of Pediatrics-1st Pediatric Discipline, Center for Research on Growth and Developmental Disorders in Children, ‘Victor Babeș’ University of Medicine and Pharmacy Timișoara, Eftimie Murgu Sq No 2, 300041 Timișoara, Romania;
- 1st Pediatric Clinic, ‘Louis Țurcanu’ Children’s Clinical and Emergency Hospital, Iosif Nemoianu 2, 300011 Timișoara, Romania
| | - Laura Pitulice
- Department of Biology-Chemistry, West University of Timişoara, Pestallozi 16, 300115 Timişoara, Romania;
- The Institute for Advanced Environmental Research (ICAM), Popa Şapcă 4C, 300054 Timişoara, Romania
| | - Otilia Bizerea-Spiridon
- Department of Biology-Chemistry, West University of Timişoara, Pestallozi 16, 300115 Timişoara, Romania;
- The Institute for Advanced Environmental Research (ICAM), Popa Şapcă 4C, 300054 Timişoara, Romania
| | - Tudor Voicu Moga
- Department VII of Internal Medicine-Gastroenterology Discipline, Advanced Regional Research Center in Gastroenterology and Hepatology, ‘Victor Babeș’ University of Medicine and Pharmacy Timișoara, Eftimie Murgu Sq No 2, 300041 Timișoara, Romania;
- Gastroenterology and Hepatology Clinic, ‘Pius Brînzeu’ County Emergency Clinical Hospital, Liviu Rebreanu 156, 300723 Timișoara, Romania
| |
Collapse
|
|
9
|
Liu X, Sun H, Zheng L, Zhang J, Su H, Li B, Wu Q, Liu Y, Xu Y, Song X, Yu Y. Adipose-derived miRNAs as potential biomarkers for predicting adulthood obesity and its complications: A systematic review and bioinformatic analysis. Obes Rev 2024; 25:e13748. [PMID: 38590187 DOI: 10.1111/obr.13748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 02/25/2024] [Accepted: 03/10/2024] [Indexed: 04/10/2024]
Abstract
Adipose tissue is the first and primary target organ of obesity and the main source of circulating miRNAs in patients with obesity. This systematic review aimed to analyze and summarize the generation and mechanisms of adipose-derived miRNAs and their role as early predictors of various obesity-related complications. Literature searches in the PubMed and Web of Science databases using terms related to miRNAs, obesity, and adipose tissue. Pre-miRNAs from the Human MicroRNA Disease Database, known to regulate obesity-related metabolic disorders, were combined for intersection processing. Validated miRNA targets were sorted through literature review, and enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes via the KOBAS online tool, disease analysis, and miRNA transcription factor prediction using the TransmiR v. 2.0 database were also performed. Thirty miRNAs were identified using both obesity and adipose secretion as criteria. Seventy-nine functionally validated targets associated with 30 comorbidities of these miRNAs were identified, implicating pathways such as autophagy, p53 pathways, and inflammation. The miRNA precursors were analyzed to predict their transcription factors and explore their biosynthesis mechanisms. Our findings offer potential insights into the epigenetic changes related to adipose-driven obesity-related comorbidities.
Collapse
Affiliation(s)
- Xiyan Liu
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
| | - Huayi Sun
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning, China
- Department of Colorectal Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lixia Zheng
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
| | - Jian Zhang
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, Liaoning, China
| | - Han Su
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
| | - Bingjie Li
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, Liaoning, China
| | - Qianhui Wu
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, Liaoning, China
| | - Yunchan Liu
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, Liaoning, China
| | - Yingxi Xu
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
- Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaoyu Song
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
| | - Yang Yu
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, China Medical University, Shenyang, Liaoning, China
- Health Sciences Institute, Key Laboratory of Obesity and Glucose/Lipid Associated Metabolic Diseases, China Medical University, Shenyang, Liaoning, China
| |
Collapse
|
|
10
|
Nkechika V, Zhang N, Belsham DD. The Involvement of the microRNAs miR-466c and miR-340 in the Palmitate-Mediated Dysregulation of Gonadotropin-Releasing Hormone Gene Expression. Genes (Basel) 2024; 15:397. [PMID: 38674332 PMCID: PMC11048885 DOI: 10.3390/genes15040397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/28/2024] Open
Abstract
Diets high in saturated fatty acids are associated with obesity and infertility. Palmitate, the most prevalent circulating saturated fatty acid, is sensed by hypothalamic neurons, contributing to homeostatic dysregulation. Notably, palmitate elevates the mRNA levels of gonadotropin-releasing hormone (Gnrh) mRNA and its activating transcription factor, GATA binding protein 4 (Gata4). GATA4 is essential for basal Gnrh expression by binding to its enhancer region, with Oct-1 (Oct1) and CEBP-β (Cebpb) playing regulatory roles. The pre- and post-transcriptional control of Gnrh by palmitate have not been investigated. Given the ability of palmitate to alter microRNAs (miRNAs), we hypothesized that palmitate-mediated dysregulation of Gnrh mRNA involves specific miRNAs. In the mHypoA-GnRH/GFP neurons, palmitate significantly downregulated six miRNAs (miR-125a, miR-181b, miR-340, miR-351, miR-466c and miR-503), and the repression was attenuated by co-treatment with 100 μM of oleate. Subsequent mimic transfections revealed that miR-466c significantly downregulates Gnrh, Gata4, and Chop mRNA and increases Per2, whereas miR-340 upregulates Gnrh, Gata4, Oct1, Cebpb, and Per2 mRNA. Our findings suggest that palmitate may indirectly regulate Gnrh at both the pre- and post-transcriptional levels by altering miR-466c and miR-340, which in turn regulate transcription factor expression levels. In summary, palmitate-mediated dysregulation of Gnrh and, consequently, reproductive function involves parallel transcriptional mechanisms.
Collapse
Affiliation(s)
- Vanessa Nkechika
- Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada; (V.N.); (N.Z.)
| | - Ningtong Zhang
- Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada; (V.N.); (N.Z.)
| | - Denise D. Belsham
- Department of Physiology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada; (V.N.); (N.Z.)
- Department of Medicine, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
| |
Collapse
|
|
11
|
Cunha E Rocha K, Ying W, Olefsky JM. Exosome-Mediated Impact on Systemic Metabolism. Annu Rev Physiol 2024; 86:225-253. [PMID: 38345906 DOI: 10.1146/annurev-physiol-042222-024535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2024]
Abstract
Exosomes are small extracellular vesicles that carry lipids, proteins, and microRNAs (miRNAs). They are released by all cell types and can be found not only in circulation but in many biological fluids. Exosomes are essential for interorgan communication because they can transfer their contents from donor to recipient cells, modulating cellular functions. The miRNA content of exosomes is responsible for most of their biological effects, and changes in exosomal miRNA levels can contribute to the progression or regression of metabolic diseases. As exosomal miRNAs are selectively sorted and packaged into exosomes, they can be useful as biomarkers for diagnosing diseases. The field of exosomes and metabolism is expanding rapidly, and researchers are consistently making new discoveries in this area. As a result, exosomes have great potential for a next-generation drug delivery platform for metabolic diseases.
Collapse
Affiliation(s)
- Karina Cunha E Rocha
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA;
| | - Wei Ying
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA;
| | - Jerrold M Olefsky
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA;
| |
Collapse
|
|
12
|
González-Domínguez Á, Belmonte T, González-Domínguez R. Childhood obesity, metabolic syndrome, and oxidative stress: microRNAs go on stage. Rev Endocr Metab Disord 2023; 24:1147-1164. [PMID: 37672200 PMCID: PMC10698091 DOI: 10.1007/s11154-023-09834-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/25/2023] [Indexed: 09/07/2023]
Abstract
The incidence of childhood obesity and metabolic syndrome has grown notably in the last years, becoming major public health burdens in developed countries. Nowadays, oxidative stress is well-recognized to be closely associated with the onset and progression of several obesity-related complications within the framework of a complex crosstalk involving other intertwined pathogenic events, such as inflammation, insulin disturbances, and dyslipidemia. Thus, understanding the molecular basis behind these oxidative dysregulations could provide new approaches for the diagnosis, prevention, and treatment of childhood obesity and associated disorders. In this respect, the transcriptomic characterization of miRNAs bares great potential because of their involvement in post-transcriptional modulation of genetic expression. Herein, we provide a comprehensive literature revision gathering state-of-the-art research into the association between childhood obesity, metabolic syndrome, and miRNAs. We put special emphasis on the potential role of miRNAs in modulating obesity-related pathogenic events, with particular focus on oxidative stress.
Collapse
Affiliation(s)
- Álvaro González-Domínguez
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, 11009, Spain.
| | - Thalía Belmonte
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
| | - Raúl González-Domínguez
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, 11009, Spain
| |
Collapse
|
|
13
|
Mak KWY, He W, Loganathan N, Belsham DD. Bisphenol A Alters the Levels of miRNAs That Directly and/or Indirectly Target Neuropeptide Y in Murine Hypothalamic Neurons. Genes (Basel) 2023; 14:1773. [PMID: 37761913 PMCID: PMC10530511 DOI: 10.3390/genes14091773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
The hypothalamus is a vital regulator of energy homeostasis. Orexigenic neuropeptide Y (NPY) neurons within the hypothalamus can stimulate feeding and suppress energy expenditure, and dysregulation of these neurons may contribute to obesity. We previously reported that bisphenol A (BPA), an endocrine disruptor with obesogenic properties, alters Npy transcription in hypothalamic neurons by inducing oxidative stress. We hypothesized that hypothalamic microRNAs (miRNAs), a class of small non-coding RNAs, could directly regulate Npy gene expression by binding the 3' untranslated region (UTR). Five predicted Npy-targeting miRNA candidates were uncovered through TargetScan and were detected in Npy-expressing hypothalamic neuronal cell models and hypothalamic neuronal primary cultures. BPA dysregulated the expression of a number of these hypothalamic miRNAs. We examined the effects of putative Npy-targeting miRNAs using miRNA mimics, and we found that miR-143-3p, miR-140-5p, miR-29b-1-5p, and let-7b-3p altered Npy expression in the murine hypothalamic cell lines. Importantly, miR-143-3p targets the mouse Npy 3' UTR, as detected using a luciferase construct containing the potential 3' UTR binding sites. Overall, this study established the first hypothalamic miRNA that directly targets the 3' UTR of mouse Npy, emphasizing the involvement of miRNAs in the NPY system and providing an alternative target for control of NPY levels.
Collapse
Affiliation(s)
- Kimberly W. Y. Mak
- Department of Physiology, University of Toronto, Medical Sciences Building 3247A, 1 Kings College Circle, Toronto, ON M5S 1A8, Canada; (K.W.Y.M.); (W.H.); (N.L.)
| | - Wenyuan He
- Department of Physiology, University of Toronto, Medical Sciences Building 3247A, 1 Kings College Circle, Toronto, ON M5S 1A8, Canada; (K.W.Y.M.); (W.H.); (N.L.)
| | - Neruja Loganathan
- Department of Physiology, University of Toronto, Medical Sciences Building 3247A, 1 Kings College Circle, Toronto, ON M5S 1A8, Canada; (K.W.Y.M.); (W.H.); (N.L.)
| | - Denise D. Belsham
- Department of Physiology, University of Toronto, Medical Sciences Building 3247A, 1 Kings College Circle, Toronto, ON M5S 1A8, Canada; (K.W.Y.M.); (W.H.); (N.L.)
- Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| |
Collapse
|
|
14
|
Xian N, Bai R, Guo J, Luo R, Lei H, Wang B, Zheng Y. Bioinformatics analysis to reveal the potential comorbidity mechanism in psoriasis and nonalcoholic steatohepatitis. Skin Res Technol 2023; 29:e13457. [PMID: 37753698 PMCID: PMC10474328 DOI: 10.1111/srt.13457] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 08/22/2023] [Indexed: 09/28/2023]
Abstract
PURPOSE An increasing amount of evidence suggests that psoriasis and nonalcoholic steatohepatitis (NASH) may occur simultaneously, whereas the underlying mechanisms remain unclear. Our research aims to explore the potential comorbidity mechanism in psoriasis and nonalcoholic steatohepatitis. MATERIALS AND METHODS The expression profiles of psoriasis (GSE30999, GSE13355) and NASH (GSE24807, GSE17470) were downloaded from GEO datasets. Next, common differently expressed genes (DEGs) of psoriasis and NASH were investigated. Then, GO and KEGG enrichment, protein interaction network (PPI) construction, and hub gene identification for DEGs were performed. Finally, immune cells expression, target genes predicted by common miRNAs, and transcription factors interaction analysis for hub genes were carried out. RESULTS Twenty DEGs were identified in totally. GO analysis revealed response to the virus was the most enriched term, and hepatitis C and coronavirus disease-COVID-19 infection-associated pathways were mainly enriched in KEGG. A total of eight hub genes were collected, including IFIT1, IFIT3, OAS1, HPGDS, IFI27, IFI44, CXCL10, IRF9, and 11 TFs were predicted. Then, neutrophils and monocytes were identified as immune cells that express the most hub genes. Moreover, five common miRNAs for psoriasis and NASH and one common miRNAs (hsa-miR-1305)-mRNAs (CHL1, MBNL2) network were presented. CONCLUSION CHL1 and MBNL2 may participate in the process of psoriasis and NASH via regulating hsa-miR-1305, and together with eight hub genes may be potential therapeutic targets for future treatment for the co-occurrence of these two diseases. This comprehensive bioinformatic analysis provides new insights on molecular pathogenesis and identification of potential therapeutic targets for the co-occurrence of them.
Collapse
Affiliation(s)
- Ningyi Xian
- Department of Dermatologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Ruimin Bai
- Department of Dermatologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Jiaqi Guo
- Department of Dermatologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Ruiting Luo
- Department of Dermatologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Hao Lei
- Department of Dermatologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Bingqing Wang
- Department of Dermatologythe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Yan Zheng
- Department of Dermatologythe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| |
Collapse
|
|
15
|
Kan Changez MI, Mubeen M, Zehra M, Samnani I, Abdul Rasool A, Mohan A, Wara UU, Tejwaney U, Kumar V. Role of microRNA in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH): a comprehensive review. J Int Med Res 2023; 51:3000605231197058. [PMID: 37676968 PMCID: PMC10492500 DOI: 10.1177/03000605231197058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 08/08/2023] [Indexed: 09/09/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver condition that affects people who do not overconsume alcohol. Uncertainties exist over how microRNAs (miRNAs) in the blood and liver relate to NAFLD. The aim of this narrative review was to investigate the role of miRNAs in the onset and progression of non-alcoholic steatohepatitis (NASH) from NAFLD, and explore their potential as diagnostic tools and treatment targets for NAFLD patients. Liver miRNA-34a levels were found to accurately represent the degree of liver damage, with lower levels suggesting more damage. In patients with NAFLD and severe liver fibrosis, higher levels of miRNA-193a-5p and miRNA-378d were found. Moreover, miRNA-34a, miRNA-122, and miRNA-192 levels might aid in differentiating NASH from NAFLD. Similar to this, miRNA-21 and miRNA-27 levels in rats were able to distinguish between steatosis and steatohepatitis. High-fat diets enhanced the expression of 15 distinct miRNAs in rats, and there were substantial differences in the miRNA expression patterns between obese and lean people. The results from the present review imply that miRNA microarrays and sequencing may be helpful diagnostic tools, and miRNAs may be a possible treatment target for patients with NAFLD.
Collapse
Affiliation(s)
- Mah I Kan Changez
- Department of Medicine, Quetta Institute of Medical Sciences, Quetta, Pakistan
| | - Maryam Mubeen
- Department of Medicine, Punjab Medical College, Faisalabad, Pakistan
| | - Monezahe Zehra
- Department of Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Inara Samnani
- Department of Medicine, Karachi Medical & Dental College, Karachi, Pakistan
| | | | - Anmol Mohan
- Department of Medicine, Karachi Medical & Dental College, Karachi, Pakistan
| | - Um Ul Wara
- Department of Medicine, Karachi Medical & Dental College, Karachi, Pakistan
| | - Usha Tejwaney
- Department of Pharmacy, Valley Health System, New Jersey, USA
| | - Vikash Kumar
- Department of Internal Medicine, The Brooklyn Hospital Center, New York City, NY, USA
| |
Collapse
|
|
16
|
Bartiromo M, Nardolillo M, Ferrara S, Russo G, Miraglia Del Giudice E, Di Sessa A. The challenging role of micro-RNAs in non-alcoholic fatty liver disease in children with obesity: is it time for a new era? Expert Rev Gastroenterol Hepatol 2023; 17:817-824. [PMID: 37497846 DOI: 10.1080/17474124.2023.2242245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 07/04/2023] [Accepted: 07/26/2023] [Indexed: 07/28/2023]
Abstract
INTRODUCTION As the pediatric obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in childhood. Pediatric NAFLD pathophysiology is tangled and still unclear, but insulin resistance (IR), genetics, epigenetics, oxidative stress, and inflammation act as key players. Due to the increased cardiometabolic risk of these patients, several biomarkers have been proposed for early NAFLD identification, but their clinical utility is poor. Recently, hepatic dysregulation of microRNAs (miRNAs) has been linked to metabolic dysfunction, which in turn implied in NAFLD development. Evidence on the intriguing role of miRNAs in NAFLD pathogenesis has emerging especially in at-risk children such as those with obesity. However, pediatric evidence supporting their potential use as early noninvasive NAFLD tools is still limited but promising. AREAS COVERED We provided an overview on the emerging role of miRNAs in pediatric NAFLD by addressing some issues regarding their pathophysiological link with the metabolic milieu and their role as reliable NAFLD markers in children with obesity. EXPERT OPINION Strong evidence supports a potential role of miRNAs as early biomarkers of NAFLD in children with obesity. They might represent a valid diagnostic and targeted therapeutic tool due to its close pathogenic link with the metabolic milieu.
Collapse
Affiliation(s)
- Mario Bartiromo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele Nardolillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Serena Ferrara
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppina Russo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Emanuele Miraglia Del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| |
Collapse
|
|
17
|
Behrooz M, Hajjarzadeh S, Kahroba H, Ostadrahimi A, Bastami M. Expression pattern of miR-193a, miR122, miR155, miR-15a, and miR146a in peripheral blood mononuclear cells of children with obesity and their relation to some metabolic and inflammatory biomarkers. BMC Pediatr 2023; 23:95. [PMID: 36859176 PMCID: PMC9976520 DOI: 10.1186/s12887-023-03867-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/25/2023] [Indexed: 03/03/2023] Open
Abstract
BACKGROUND The widespread presence of childhood obesity has increased considerably over three decades. The present study was designed to investigate expression patterns of miR-146a, miR-155, miR-15a, miR-193a, and miR-122 in peripheral blood mononuclear cells (PBMCs) in children who are obese along with their association with metabolic and inflammatory biomarkers. METHODS Ninety test subjects were admitted. The profile of blood pressure, resting energy expenditure (REE), anthropometric measures, body composition, dietary intakes, physical activity levels, insulin, and lipid profile, fasting blood glucose (FBG), high-sensitivity C-reactive protein (hs-CRP), and pubertal stage have been measured. Total RNA (including small RNAs) was extracted from PBMCs. The expression levels of miRNAs were measured by stem-loop RT-qPCR. RESULTS The miR-155a expression level was significantly lower in obese children, children with high hs-CRP, and children with high-fat mass. Obese girls had significantly higher PBMC levels of miR-122. MiR-155a had a significant negative association with fasting insulin, HOMA-IR, and hs-CRP. There were significant positive associations between miR-193a and miR-122 expression levels and fasting insulin, HOMA-IR, and TG. MiR-15a was positively correlated with fasting insulin and HOMA-IR. Children with metabolic syndrome, insulin resistance, and high-fat mass had higher PBMC levels of miR-122 and miR-193a. Higher miR-193a and miR-122 levels were also detected in PBMCs of children with fast REE, compared to those with slow REE, and the subjects with high hs-CRP, respectively. CONCLUSION lower level of miR-155 expression in obese subjects and significant associations unfolds the need for more studies to detect the possible underlying mechanisms.
Collapse
Affiliation(s)
- Maryam Behrooz
- Department of Clinical Nutrition, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Pediatric Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samaneh Hajjarzadeh
- Student of Nutrition Sciences. Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Houman Kahroba
- Department of Toxicogenomics, GROW School of Oncology and Development Biology, Maastricht University, Maastricht, Netherlands.,Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Alireza Ostadrahimi
- Department of Clinical Nutrition, Nutrition Research Center, School of Nutrition & Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Milad Bastami
- Department of Medical Genetics, Tabriz University of Medical Sciences, Golgasht St, Attar Neyshabouri Av, Tabriz, Iran.
| |
Collapse
|
|
18
|
Hussain SRA, Grayson MH. Chronic allergy signaling: is it all stressed-out mitochondria? Fac Rev 2022; 11:37. [PMID: 36644297 PMCID: PMC9816874 DOI: 10.12703/r/11-37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Allergic diseases in general, and chronic allergic inflammation in particular, are on the rise in the United States and other developed countries. The idea of chronic allergic disease as a chronic type 2 immune response has been around for several decades. However, data suggest that other mechanisms may be important in chronic disease. Therefore, we believe it is time for a paradigm shift in understanding the mechanistic causes of disease symptoms in these diseases. In this review, we have avoided the classic canonical pathways and focused on the emerging idea that oxidative stress, changes in immuno-metabolism, mitochondrial dysfunction, and epigenetic changes (particularly microRNA profile) may be working concurrently or synergistically to potentiate allergic disease symptoms. Furthermore, we have addressed how the epidemic of obesity exacerbates allergic disease via the dysregulation of the aforementioned factors.
Collapse
Affiliation(s)
- Syed-Rehan A Hussain
- Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children’s Hospital - The Ohio State University College of Medicine, Columbus, OH, USA
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
- mailto:
| | - Mitchell H Grayson
- Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children’s Hospital - The Ohio State University College of Medicine, Columbus, OH, USA
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| |
Collapse
|
|
19
|
Khaliltahmasebi R, Minasian V, Hovsepian S. Effects of Two Different School-Based Training on Serum miR15b Expression and Lipid Profile of Adolescents with Obesity. Int J Prev Med 2022; 13:139. [PMID: 36618534 PMCID: PMC9811960 DOI: 10.4103/ijpvm.ijpvm_6_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 09/28/2021] [Indexed: 01/10/2023] Open
Abstract
Background Some circulating microRNAs, such as miR15b, are predictors of diseases associated with adulthood obesity. This study aimed to evaluate the effect of two selected school-based and high-intensity interval training (HIT) on miR15b expression and lipid profile of obese adolescents. Methods Thirty-eight adolescent males (12 ± 1 years) with obesity (body mass: 74.7 ± 13.2 kg, body mass index (BMI): 26.0 ± 2.3 kg/m2, and body fat (BF): 27.2 ± 3.6%) were randomly assigned to the following based on the age-related body mass index: (i) HIT (n = 13), (ii) school-based exercises (SBE, n = 13), and (iii) control (n = 12) groups. Mir15b was extracted using the RT-PCR system, and lipid profile was studied using the enzymatic colorimetric method before and after 12 weeks. Three training sessions were held each week during the course. Results Following the exercise interventions, in both training groups, miR15b (HIT: -63.8 vs. SBE: -56. 7%; P = 0.001), cholesterol (HIT: -8.8 vs. SBE: -9.2%; P = 0.025), and low-density lipoproteins levels (SBE: -13.1 vs. -20.8%; P = 0.48) decreased; however, the peak oxygen uptake of subjects increased (HIT: 4.0 vs. SBE: 4.0%; P = 0.003). However, there were no significant differences in triglyceride (HIT: -16.9 vs. SBE: -8.3%; P = 0.134), and high-density lipoprotein (HIT: 3.1 vs. SBE: 4.8%; P = 0.479) levels between both intervention and control groups (P > 0.05). Conclusions The results showed that both types of exercises had almost similar effects on reducing miR15b expression and improving the lipid profile. Hence, based on the difficult nature of HIT for children with obesity, further use of school-based exercises is suggested.
Collapse
Affiliation(s)
- Rasol Khaliltahmasebi
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran
| | - Vazgen Minasian
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran,Address for correspondence: Dr. Vazgen Minasian, Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran. E-mail:
| | - Silva Hovsepian
- Metabolic Liver Diseases Research Center, Imam Hossein Children's Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
20
|
Brandão-Lima PN, de Carvalho GB, Payolla TB, Sarti FM, Rogero MM. Circulating microRNA Related to Cardiometabolic Risk Factors for Metabolic Syndrome: A Systematic Review. Metabolites 2022; 12:1044. [PMID: 36355127 PMCID: PMC9692352 DOI: 10.3390/metabo12111044] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 01/04/2024] Open
Abstract
MicroRNA regulates multiple pathways in inflammatory response, adipogenesis, and glucose and lipid metabolism, which are involved in metabolic syndrome (MetS). Thus, this systematic review aimed at synthesizing the evidence on the relationships between circulating microRNA and risk factors for MetS. The systematic review was registered in the PROSPERO database (CRD42020168100) and included 24 case-control studies evaluating microRNA expression in serum/plasma of individuals ≥5 years old. Most of the studies focused on 13 microRNAs with higher frequency and there were robust connections between miR-146a and miR-122 with risk factors for MetS, based on average weighted degree. In addition, there was an association of miR-222 with adiposity, lipid metabolism, glycemic metabolism, and chronic inflammation and an association of miR-126, miR-221, and miR-423 with adiposity, lipid, and glycemic metabolism. A major part of circulating microRNA was upregulated in individuals with risk factors for MetS, showing correlations with glycemic and lipid markers and body adiposity. Circulating microRNA showed distinct expression profiles according to the clinical condition of individuals, being particularly linked with increased body fat. However, the exploration of factors associated with variations in microRNA expression was limited by the variety of microRNAs investigated by risk factor in diverse studies identified in this systematic review.
Collapse
Affiliation(s)
- Paula N. Brandão-Lima
- Department of Nutrition, School of Public Health, University of Sao Paulo, 715 Dr Arnaldo Avenue, Pacaembu, Sao Paulo 01246-904, SP, Brazil
| | - Gabrielli B. de Carvalho
- Department of Nutrition, School of Public Health, University of Sao Paulo, 715 Dr Arnaldo Avenue, Pacaembu, Sao Paulo 01246-904, SP, Brazil
| | - Tanyara B. Payolla
- Department of Nutrition, School of Public Health, University of Sao Paulo, 715 Dr Arnaldo Avenue, Pacaembu, Sao Paulo 01246-904, SP, Brazil
| | - Flavia M. Sarti
- School of Arts, Sciences and Humanities, University of Sao Paulo, 1000 Arlindo Bettio Avenue, Sao Paulo 03828-000, SP, Brazil
| | - Marcelo M. Rogero
- Department of Nutrition, School of Public Health, University of Sao Paulo, 715 Dr Arnaldo Avenue, Pacaembu, Sao Paulo 01246-904, SP, Brazil
| |
Collapse
|
|
21
|
Zaiou M. Noncoding RNAs as additional mediators of epigenetic regulation in nonalcoholic fatty liver disease. World J Gastroenterol 2022; 28:5111-5128. [PMID: 36188722 PMCID: PMC9516672 DOI: 10.3748/wjg.v28.i35.5111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 07/28/2022] [Accepted: 08/25/2022] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common cause of chronic liver disorder worldwide. It represents a spectrum that includes a continuum of different clinical entities ranging from simple steatosis to nonalcoholic steatohepatitis, which can evolve to cirrhosis and in some cases to hepatocellular carcinoma, ultimately leading to liver failure. The pathogenesis of NAFLD and the mechanisms underlying its progression to more pathological stages are not completely understood. Besides genetic factors, evidence indicates that epigenetic mechanisms occurring in response to environmental stimuli also contribute to the disease risk. Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, are one of the epigenetic factors that play key regulatory roles in the development of NAFLD. As the field of ncRNAs is rapidly evolving, the present review aims to explore the current state of knowledge on the roles of these RNA species in the pathogenesis of NAFLD, highlight relevant mechanisms by which some ncRNAs can modulate regulatory networks implicated in NAFLD, and discuss key challenges and future directions facing current research in the hopes of developing ncRNAs as next-generation non-invasive diagnostics and therapies in NAFLD and subsequent progression to hepatocellular carcinoma.
Collapse
Affiliation(s)
- Mohamed Zaiou
- Institut Jean Lamour, UMR CNRS 7198, CNRS, University of Lorraine, Nancy 54011, France
| |
Collapse
|
|
22
|
Ojeda‐Rodríguez A, Assmann TS, Alonso‐Pedrero L, Azcona‐Sanjulian MC, Milagro FI, Marti A. Circulating miRNAs in girls with abdominal obesity: miR-221-3p as a biomarker of response to weight loss interventions. Pediatr Obes 2022; 17:e12910. [PMID: 35289984 PMCID: PMC9539627 DOI: 10.1111/ijpo.12910] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 12/23/2021] [Accepted: 02/13/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent studies have associated several microRNAs (miRNAs) with childhood obesity and energy homeostasis, suggesting that an individual miRNA profile could be used as an early predictor to estimate the response to weight loss interventions in the design of precision nutrition. OBJECTIVE To investigate associations between the expression of circulating adiposity-related miRNAs and the response to a weight loss intervention. METHODS A total of 51 Spanish girls (age 7-16 years) with abdominal obesity underwent 8 weeks of a multidisciplinary intervention for weight loss. Participants were stratified into two groups in accordance with changes in body mass index (BMI) standard deviation score: low-responders (LR) and high-responders (HR). The expression of 39 circulating miRNAs (c-miRNAs) was evaluated in plasma of all subjects before the intervention. RESULTS Six miRNAs were differentially expressed between LR and HR. However, after adjustment for Tanner stage, the association was maintained only for miR-126-3p and miR-221-3p with a higher expression in HR group compared to LR group. After the intervention, miR-221-3p expression decreased in all subjects with a significant difference in the change within groups. However, changes in miR-126-3p levels were not significant. The expression of miR-221-3p was positively correlated with body weight, BMI and waist circumference, and negatively correlated with quantitative insulin sensitivity check index. CONCLUSIONS Bioinformatic analysis evidenced that miR-221-3p participates in several obesity-related pathways, and more interestingly, this miRNA targets several candidate genes to childhood obesity according to DisGeNet database. Thus, miR-221-3p could be used for predicting the response to a multidisciplinary intervention for weight loss in young girls.
Collapse
Affiliation(s)
- Ana Ojeda‐Rodríguez
- Department of Nutrition, Food Sciences and PhysiologyUniversity of NavarraPamplonaSpain,IdiSNA, Instituto de Investigación Sanitaria de NavarraPamplonaSpain
| | - Taís Silveira Assmann
- Department of Nutrition, Food Sciences and PhysiologyUniversity of NavarraPamplonaSpain,Endocrinology, Faculty of MedicineFederal University of Rio Grande do SulPorto AlegreBrazil
| | - Lucia Alonso‐Pedrero
- Department of Nutrition, Food Sciences and PhysiologyUniversity of NavarraPamplonaSpain,IdiSNA, Instituto de Investigación Sanitaria de NavarraPamplonaSpain
| | - Maria Cristina Azcona‐Sanjulian
- IdiSNA, Instituto de Investigación Sanitaria de NavarraPamplonaSpain,Pediatric Endocrinology Unit, Department of PediatricsClínica Universidad de NavarraPamplonaSpain
| | - Fermín I. Milagro
- Department of Nutrition, Food Sciences and PhysiologyUniversity of NavarraPamplonaSpain,IdiSNA, Instituto de Investigación Sanitaria de NavarraPamplonaSpain,Center for Nutrition ResearchUniversity of NavarraPamplonaSpain,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn)Physiopathology of Obesity and Nutrition, Institute of Health Carlos IIIMadridSpain
| | - Amelia Marti
- Department of Nutrition, Food Sciences and PhysiologyUniversity of NavarraPamplonaSpain,IdiSNA, Instituto de Investigación Sanitaria de NavarraPamplonaSpain,Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBERobn)Physiopathology of Obesity and Nutrition, Institute of Health Carlos IIIMadridSpain
| |
Collapse
|
|
23
|
Ding J, Xia C, Cen P, Li S, Yu L, Zhu J, Jin J. MiR-103-3p promotes hepatic steatosis to aggravate nonalcoholic fatty liver disease by targeting of ACOX1. Mol Biol Rep 2022; 49:7297-7305. [PMID: 35606603 PMCID: PMC9304065 DOI: 10.1007/s11033-022-07515-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/25/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for hepatocellular carcinoma, and alterations in miRNA expression are related to the development of NAFLD. However, the role of miRNAs in regulating the development of NAFLD is still poorly understood. METHODS We used qRT-PCR to detect the level of miR-103-3p in both cell and mouse models of NAFLD. Biochemical assays, DCF-DA assays, Oil red O staining and HE staining were used to detect the role of miR-103-3p in NAFLD development. Target genes of miR-103-3p were predicted using the TargetScan database and verified by qRT-PCR, western blot and dual-luciferase assays. RESULTS The expression of miR-103-3p increased in both NAFLD model cells and liver tissues from the NAFLD mouse model. Inhibition of miR-103-3p significantly alleviated the accumulation of lipid droplets in free fatty acid-treated L02 cells and liver tissues from mice with NAFLD. Inhibition of miR-103-3p reduced the contents of H2O2, TG, ALT, and AST and ROS production while increasing the ATP content. Moreover, the miR-103-3p antagomir alleviated liver tissue lesions in mice with NAFLD. Further studies identified ACOX1, a key enzyme for the oxidation and decomposition of fatty acids, as a direct target of miR-103-3p. CONCLUSIONS These findings identified a negative regulatory mechanism between ACOX1 and miR-103-3p that promotes the pathogenesis of NAFLD and suggested that inhibition of miR-103-3p may be a potential treatment strategy for NAFLD.
Collapse
Affiliation(s)
- Jiexia Ding
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310003, Zhejiang Province, China
| | - Caixia Xia
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310003, Zhejiang Province, China
| | - Panpan Cen
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310003, Zhejiang Province, China
| | - Siying Li
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310003, Zhejiang Province, China
| | - Lifei Yu
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310003, Zhejiang Province, China
| | - Jing Zhu
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310003, Zhejiang Province, China.
| | - Jie Jin
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310003, Zhejiang Province, China.
| |
Collapse
|
|
24
|
Heo Y, Kim H, Lim J, Choi SS. Adipocyte differentiation between obese and lean conditions depends on changes in miRNA expression. Sci Rep 2022; 12:11543. [PMID: 35798800 PMCID: PMC9262987 DOI: 10.1038/s41598-022-15331-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 06/22/2022] [Indexed: 12/03/2022] Open
Abstract
Adipogenesis is the process by which precursor cells, preadipocytes (preACs), differentiate into adipocytes (ACs). Here, we investigated differentially expressed miRNAs (DEMs) between the two conditions to understand the regulatory role of miRNAs in altering adipogenesis-related mRNAs. A total of 812 and 748 DEMs were obtained in lean and obese conditions, respectively. The up- and downregulated DEMs were highly concordant with each other in both lean and obese conditions; however, DEMs related to adipogenesis in obese conditions were more strongly downregulated than DEMs related to adipogenesis in lean conditions. There were more obese-specific downregulated DEMs than lean-specific downregulated DEMs; in contrast, there were more lean-specific upregulated DEMs than obese-specific upregulated DEMs. Approximately 45% of DEMs were mapped to the list of miRNA-target mRNA pairs when DEMs were matched to the experimentally validated list of miRNA-target mRNA information of miRTarBase. Many of the target mRNAs were differentially expressed genes (DEGs) with functions in processes such as inflammatory responses and fat metabolism. In particular, a total of 25 miRNAs that target three upregulated adipogenesis-associated inflammatory genes (IL-6, TNF-α, and IL-1β) were commonly altered during adipogenesis. Taken together, our study reveals the types of adipogenesis-related miRNAs that are altered and the degree to which they influence healthy or pathogenic adipogenesis.
Collapse
Affiliation(s)
- Yerim Heo
- Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, 24341, Korea
| | - Hyunjung Kim
- Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, 24341, Korea
| | - Jiwon Lim
- Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, 24341, Korea
| | - Sun Shim Choi
- Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, 24341, Korea.
| |
Collapse
|
|
25
|
MicroRNA-Based Diagnosis and Therapy. Int J Mol Sci 2022; 23:ijms23137167. [PMID: 35806173 PMCID: PMC9266664 DOI: 10.3390/ijms23137167] [Citation(s) in RCA: 309] [Impact Index Per Article: 103.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results in changes in the profile of genes involving a range of biological processes, contributing to numerous human disorders. With high stability in human fluids, miRNAs in the circulation are considered as promising biomarkers for diagnosis, as well as prognosis of disease. In addition, the translation of miRNA-based therapy from a research setting to clinical application has huge potential. The aim of the current review is to: (i) discuss how miRNAs traffic intracellularly and extracellularly; (ii) emphasize the role of circulating miRNAs as attractive potential biomarkers for diagnosis and prognosis; (iii) describe how circulating microRNA can be measured, emphasizing technical problems that may influence their relative levels; (iv) highlight some of the circulating miRNA panels available for clinical use; (v) discuss how miRNAs could be utilized as novel therapeutics, and finally (v) update those miRNA-based therapeutics clinical trials that could potentially lead to a breakthrough in the treatment of different human pathologies.
Collapse
|
|
26
|
Hutny M, Hofman J, Zachurzok A, Matusik P. MicroRNAs as the promising markers of comorbidities in childhood obesity-A systematic review. Pediatr Obes 2022; 17:e12880. [PMID: 34918493 PMCID: PMC9285424 DOI: 10.1111/ijpo.12880] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 11/01/2021] [Accepted: 12/03/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Rising child obesity rate creates a need for tools quantifying changes in children suffering from obesity, for purposes of detection or prevention of comorbidities. A candidate for such a role seems to be microRNAs, which in vivo serve as the suppressing factors in gene expression. OBJECTIVES This study aimed at reviewing recent discoveries in this field and concluding directions of research or application of studied molecules. METHODS Repeated browsing of databases and screening of results, led to final approval of 16 articles. Filtered studies examined differences in microRNA expression between subjects with obesity and children suffering from its comorbidities. RESULTS Studies concerning endothelial dysfunction identified molecules miR-320a and miR-630 as a possible diagnosis and treatment option. Search for the alternative markers in diagnosis of non-alcoholic fatty liver disease suggested value of molecules: miR-199a-5p and miR-122. miR-486, miR-146b, and miR-15b may serve in grading the development of type 2 diabetes in children, although further research raised doubts. Panel of molecules was indicated as useful in early detection of metabolic syndrome and insulin resistance associated alterations. No valid link between studied microRNAs and atherosclerosis was found. CONCLUSIONS MicroRNAs seem to be promising prognostic markers for diagnosis of endothelial dysfunction, non-alcoholic fatty liver disease, type 2 diabetes, metabolic syndrome and insulin resistance in children.
Collapse
Affiliation(s)
- Michał Hutny
- Scientific Society of Medical Students, Faculty of Medical Sciences in KatowiceMedical University of SilesiaKatowicePoland
| | - Jagoda Hofman
- Scientific Society of Medical Students, Faculty of Medical Sciences in KatowiceMedical University of SilesiaKatowicePoland
| | - Agnieszka Zachurzok
- Department of Pediatrics, Faculty of Medical Sciences in ZabrzeMedical University of SilesiaKatowicePoland
| | - Paweł Matusik
- Department of Pediatrics, Pediatric Obesity and Metabolic Bone Diseases, Chair of Pediatrics and Pediatric Endocrinology, Faculty of Medical Sciences in KatowiceMedical University of SilesiaKatowicePoland
| |
Collapse
|
|
27
|
Dietary Improvement during Lactation Normalizes miR-26a, miR-222 and miR-484 Levels in the Mammary Gland, but Not in Milk, of Diet-Induced Obese Rats. Biomedicines 2022; 10:biomedicines10061292. [PMID: 35740314 PMCID: PMC9219892 DOI: 10.3390/biomedicines10061292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 05/24/2022] [Accepted: 05/24/2022] [Indexed: 02/01/2023] Open
Abstract
We aimed to evaluate in rats whether the levels of specific miRNA are altered in the mammary gland (MG) and milk of diet-induced obese dams, and whether improving maternal nutrition during lactation attenuates such alterations. Dams fed with a standard diet (SD) (control group), with a Western diet (WD) prior to and during gestation and lactation (WD group), or with WD prior to and during gestation but moved to SD during lactation (Rev group) were followed. The WD group showed higher miR-26a, miR-222 and miR-484 levels than the controls in the MG, but the miRNA profile in Rev animals was not different from those of the controls. The WD group also displayed higher miR-125a levels than the Rev group. Dams of the WD group, but not the Rev group, displayed lower mRNA expression levels of Rb1 (miR-26a’s target) and Elovl6 (miR-125a’s target) than the controls in the MG. The WD group also presented lower expression of Insig1 (miR-26a’s target) and Cxcr4 (miR-222’s target) than the Rev group. However, both WD and Rev animals displayed lower expression of Vegfa (miR-484’s target) than the controls. WD animals also showed greater miR-26a, miR-125a and miR-222 levels in the milk than the controls, but no differences were found between the WD and Rev groups. Thus, implementation of a healthy diet during lactation normalizes the expression levels of specific miRNAs and some target genes in the MG of diet-induced obese dams but not in milk.
Collapse
|
|
28
|
Time-Restricted Eating Regimen Differentially Affects Circulatory miRNA Expression in Older Overweight Adults. Nutrients 2022; 14:nu14091843. [PMID: 35565812 PMCID: PMC9100641 DOI: 10.3390/nu14091843] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/19/2022] [Accepted: 04/25/2022] [Indexed: 02/01/2023] Open
Abstract
Time-restricted eating (TRE), a popular form of intermittent fasting, has been demonstrated to provide multiple health benefits, including an extension of healthy lifespan in preclinical models. While the specific mechanisms remain elusive, emerging research indicates that one plausible mechanism through which TRE may confer health benefits is by influencing the expression of the epigenetic modulator circulatory miRNAs, which serve as intercellular communicators and are dysregulated in metabolic disorders, such as obesity. Therefore, the goal of this pilot study is to examine the effects of a 4-week TRE regimen on global circulatory miRNA from older (≥65 years) overweight participants. Pre- and post-TRE regimen serum samples from nine individuals who participated in the Time to Eat clinical trial (NCT03590847) and had a significant weight loss (2.6 kg, p < 0.01) were analyzed. The expressions of 2083 human miRNAs were quantified using HTG molecular whole transcriptome miRNA assay. In silico analyses were performed to determine the target genes and biological pathways associated with differentially expressed miRNAs to predict the metabolic effects of the TRE regimen. Fourteen miRNAs were differentially expressed pre- and post-TRE regimen. Specifically, downregulated miRNA targets suggested increased expression of transcripts, including PTEN, TSC1, and ULK1, and were related to cell growth and survival. Furthermore, the targets of downregulated miRNAs were associated with Ras signaling (cell growth and proliferation), mTOR signaling (cell growth and protein synthesis), insulin signaling (glucose uptake), and autophagy (cellular homeostasis and survival). In conclusion, the TRE regimen downregulated miRNA, which, in turn, could inhibit the pathways of cell growth and activate the pathways of cell survival and might promote healthy aging. Future mechanistic studies are required to understand the functional role of the miRNAs reported in this study.
Collapse
|
|
29
|
Pérez-García A, Torrecilla-Parra M, Fernández-de Frutos M, Martín-Martín Y, Pardo-Marqués V, Ramírez CM. Posttranscriptional Regulation of Insulin Resistance: Implications for Metabolic Diseases. Biomolecules 2022; 12:biom12020208. [PMID: 35204710 PMCID: PMC8961590 DOI: 10.3390/biom12020208] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 12/14/2022] Open
Abstract
Insulin resistance defines an impairment in the biologic response to insulin action in target tissues, primarily the liver, muscle, adipose tissue, and brain. Insulin resistance affects physiology in many ways, causing hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperinsulinemia, elevated inflammatory markers, and endothelial dysfunction, and its persistence leads to the development metabolic disease, including diabetes, obesity, cardiovascular disease, or nonalcoholic fatty liver disease (NAFLD), as well as neurological disorders such as Alzheimer’s disease. In addition to classical transcriptional factors, posttranscriptional control of gene expression exerted by microRNAs and RNA-binding proteins constitutes a new level of regulation with important implications in metabolic homeostasis. In this review, we describe miRNAs and RBPs that control key genes involved in the insulin signaling pathway and related regulatory networks, and their impact on human metabolic diseases at the molecular level, as well as their potential use for diagnosis and future therapeutics.
Collapse
|
|
30
|
Močnik M, Marčun Varda N. Current Knowledge of Selected Cardiovascular Biomarkers in Pediatrics: Kidney Injury Molecule-1, Salusin-α and -β, Uromodulin, and Adropin. CHILDREN 2022; 9:children9010102. [PMID: 35053727 PMCID: PMC8774650 DOI: 10.3390/children9010102] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 01/01/2022] [Accepted: 01/10/2022] [Indexed: 02/06/2023]
Abstract
Cardiovascular diseases are the leading cause of morbidity and mortality in the modern world. Their common denominator is atherosclerosis, a process beginning in childhood. In pediatrics, the aim of preventive measures is to recognize children and adolescents at risk for accelerated atherosclerosis and possible premature cardiovascular events in adulthood. Several diagnostic procedures and biomarkers are available for cardiovascular risk assessment in adults. However, reliable markers in pediatrics are still insufficiently studied. In this contribution, we discuss five potential biomarkers of particular interest: kidney injury molecule-1, salusin-α and -β, uromodulin, and adropin. Studies regarding the pediatric population are scarce, but they support the evidence from studies in the adult population. These markers might entail both a prognostic and a therapeutic interest.
Collapse
Affiliation(s)
- Mirjam Močnik
- Department of Paediatrics, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia;
- Correspondence:
| | - Nataša Marčun Varda
- Department of Paediatrics, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia;
- Medical Faculty, University of Maribor, Taborska 8, 2000 Maribor, Slovenia
| |
Collapse
|
|
31
|
Alfano R, Robinson O, Handakas E, Nawrot TS, Vineis P, Plusquin M. Perspectives and challenges of epigenetic determinants of childhood obesity: A systematic review. Obes Rev 2022; 23 Suppl 1:e13389. [PMID: 34816569 DOI: 10.1111/obr.13389] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/20/2022]
Abstract
The tremendous increase in childhood obesity prevalence over the last few decades cannot merely be explained by genetics and evolutionary changes in the genome, implying that gene-environment interactions, such as epigenetic modifications, likely play a major role. This systematic review aims to summarize the evidence of the association between epigenetics and childhood obesity. A literature search was performed via PubMed and Scopus engines using a combination of terms related to epigenetics and pediatric obesity. Articles studying the association between epigenetic mechanisms (including DNA methylation and hydroxymethylation, non-coding RNAs, and chromatin and histones modification) and obesity and/or overweight (or any related anthropometric parameters) in children (0-18 years) were included. The risk of bias was assessed with a modified Newcastle-Ottawa scale for non-randomized studies. One hundred twenty-one studies explored epigenetic changes related to childhood obesity. DNA methylation was the most widely investigated mechanism (N = 101 studies), followed by non-coding RNAs (N = 19 studies) with evidence suggestive of an association with childhood obesity for DNA methylation of specific genes and microRNAs (miRNAs). One study, focusing on histones modification, was identified. Heterogeneity of findings may have hindered more insights into the epigenetic changes related to childhood obesity. Gaps and challenges that future research should face are herein described.
Collapse
Affiliation(s)
- Rossella Alfano
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.,Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, UK.,Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Oliver Robinson
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.,Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, UK
| | - Evangelos Handakas
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.,Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, UK
| | - Tim S Nawrot
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - Paolo Vineis
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.,Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, UK.,Unit of Molecular and Genetic Epidemiology, Human Genetic Foundation (HuGeF), Turin, Italy
| | - Michelle Plusquin
- Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| |
Collapse
|
|
32
|
Current understanding of the role of microRNAs from adipose-derived extracellular vesicles in obesity. Biochem Soc Trans 2021; 50:447-457. [PMID: 34940800 DOI: 10.1042/bst20211031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 11/17/2022]
Abstract
Obesity and its associated metabolic diseases, including diabetes, insulin resistance, and inflammation, are rapidly becoming a global health concern. Moreover, obese individuals are more likely to be infected with COVID-19. New research on adipose tissue is required to help us understand these metabolic diseases and their regulatory processes. Recently, extracellular vesicles (EVs) have been identified as novel intercellular vectors with a wide range of regulatory functions. The miRNAs carried by EVs participate in the regulation of white adipose tissue (WAT) browning, insulin resistance, diabetes, and inflammation. In addition, EV miRNAs demonstrate great potential for helping elucidating the mechanism of metabolic diseases, and for advancing their prevention and treatment. In this review, we focus on the mechanisms underlying the regulation of adipose differentiation and metabolic diseases by adipose-derived EV miRNAs. Understanding the role of these miRNAs should enrich our understanding of the etiology and pathogenesis of metabolic diseases caused by obesity.
Collapse
|
|
33
|
The Relationship between Body Mass Index, Obesity, and LINE-1 Methylation: A Cross-Sectional Study on Women from Southern Italy. DISEASE MARKERS 2021; 2021:9910878. [PMID: 34900031 PMCID: PMC8664509 DOI: 10.1155/2021/9910878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/18/2021] [Accepted: 11/10/2021] [Indexed: 11/17/2022]
Abstract
Uncovering the relationship between body mass index (BMI) and DNA methylation could be useful to understand molecular mechanisms underpinning the effects of obesity. Here, we presented a cross-sectional study, aiming to evaluate the association of BMI and obesity with long interspersed nuclear elements (LINE-1) methylation, among 488 women from Catania, Italy. LINE-1 methylation was assessed in leukocyte DNA by pyrosequencing. We found a negative association between BMI and LINE-1 methylation level in both the unadjusted and adjusted linear regression models. Accordingly, obese women exhibited lower LINE-1 methylation level than their normal weight counterpart. This association was confirmed after adjusting for the effect of age, educational level, employment status, marital status, parity, menopause, and smoking status. Our findings were in line with previous evidence and encouraged further research to investigate the potential role of DNA methylation markers in the management of obesity.
Collapse
|
|
34
|
Abstract
Abstract
Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease, worldwide. The molecular pathogenesis of NAFLD is complex, involving numerous signalling molecules including microRNAs (miRNAs). Dysregulation of miRNA expression is associated with hepatic inflammation, fibrosis and hepatocellular carcinoma. Although miRNAs are also critical to the cellular response to vitamin D, mediating regulation of the vitamin D receptor (VDR) and vitamin D’s anticancer effects, a role for vitamin D regulated miRNAs in NAFLD pathogenesis has been relatively unexplored. Therefore, this review aimed to critically assess the evidence for a potential subset of miRNAs that are both dysregulated in NAFLD and modulated by vitamin D. Comprehensive review of 89 human studies identified 25 miRNAs found dysregulated in more than one NAFLD study. In contrast, only 17 studies, including a protocol for a trial in NAFLD, had examined miRNAs in relation to vitamin D status, response to supplementation, or vitamin D in the context of the liver. This paper summarises these data and reviews the biological roles of six miRNAs (miR-21, miR-30, miR-34, miR-122, miR-146, miR-200) found dysregulated in multiple independent NAFLD studies. While modulation of miRNAs by vitamin D has been understudied, integrating the data suggests seven vitamin D modulated miRNAs (miR-27, miR-125, miR-155, miR-192, miR-223, miR-375, miR-378) potentially relevant to NAFLD pathogenesis. Our summary tables provide a significant resource to underpin future hypothesis-driven research, and we conclude that the measurement of serum and hepatic miRNAs in response to vitamin D supplementation in larger trials is warranted.
Collapse
|
|
35
|
Causative Mechanisms of Childhood and Adolescent Obesity Leading to Adult Cardiometabolic Disease: A Literature Review. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app112311565] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The past few decades have shown a worrisome increase in the prevalence of obesity and its related illnesses. This increasing burden has a noteworthy impact on overall worldwide mortality and morbidity, with significant economic implications as well. The same trend is apparent regarding pediatric obesity. This is a particularly concerning aspect when considering the well-established link between cardiovascular disease and obesity, and the fact that childhood obesity frequently leads to adult obesity. Moreover, most obese adults have a history of excess weight starting in childhood. In addition, given the cumulative character of both time and severity of exposure to obesity as a risk factor for associated diseases, the repercussions of obesity prevalence and related morbidity could be exponential in time. The purpose of this review is to outline key aspects regarding the current knowledge on childhood and adolescent obesity as a cardiometabolic risk factor, as well as the most common etiological pathways involved in the development of weight excess and associated cardiovascular and metabolic diseases.
Collapse
|
|
36
|
Ramírez-Mejía MM, Díaz-Orozco LE, Barranco-Fragoso B, Méndez-Sánchez N. A Review of the Increasing Prevalence of Metabolic-Associated Fatty Liver Disease (MAFLD) in Children and Adolescents Worldwide and in Mexico and the Implications for Public Health. Med Sci Monit 2021; 27:e934134. [PMID: 34456329 PMCID: PMC8415038 DOI: 10.12659/msm.934134] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/17/2021] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects almost a quarter of the world's population and is the most common cause of chronic liver disease in children and adolescents. The recent proposal to replace the terminology of NAFLD with metabolic-associated fatty liver disease (MAFLD) aims to reflect the pathophysiology and risk factors for this disease. Importantly, the risk factors for MAFLD may be prenatal, such as genetic factors, or postnatal, such as obesity and insulin resistance. MAFLD is increasingly recognized in children and adolescents. Early diagnosis and identification of high-risk individuals with type 2 diabetes mellitus and metabolic syndrome is important. The diagnosis and management of MAFLD in children and adolescents should follow international clinical guidelines, such as those from the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD). Current guidelines recommend lifestyle and dietary modifications, exercise, screening, individualized patient assessment, and multidisciplinary patient management. This review assesses the revised terminology and discusses the epidemiology, risk factors, pathophysiology, diagnosis, and prevention of MAFLD in children and adolescents worldwide and in Mexico, and also considers the implications for public health.
Collapse
Affiliation(s)
- Mariana M. Ramírez-Mejía
- Plan of Combined Studies in Medicine (PECEM-MD/PhD), Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Luis E. Díaz-Orozco
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
| | - Beatriz Barranco-Fragoso
- Department of Gastroenterology, National Medical Center “20 de Noviembre”, ISSSTE, Mexico City, Mexico
| | - Nahum Méndez-Sánchez
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City, Mexico
| |
Collapse
|
|
37
|
Karere GM, Cox LA, Bishop AC, South AM, Shaltout HA, Mercado-Deane MG, Cuda S. Sex Differences in MicroRNA Expression and Cardiometabolic Risk Factors in Hispanic Adolescents with Obesity. J Pediatr 2021; 235:138-143.e5. [PMID: 33831442 PMCID: PMC8926296 DOI: 10.1016/j.jpeds.2021.03.070] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To evaluate sex differences in microRNA (miRNA) expression, anthropometric measures, and cardiometabolic risk factors in Hispanic adolescents with obesity. STUDY DESIGN Cross-sectional study of 68 (60% male) Hispanic adolescents with obesity, aged 13-17 years, recruited from a pediatric weight management clinic. We used small RNA sequencing to identify differentially expressed circulating miRNAs. We used ingenuity pathway analysis and David bioinformatic resource tools to identify target genes for these miRNAs and enriched pathways. We used standard procedures to measure anthropometric and cardiometabolic factors. RESULTS We identified 5 miRNAs (miR-24-3p, miR-361-3p, miR-3605-5p, miR-486-5p, and miR-199b-3p) that differed between females and males. miRNA targets-enriched pathways included phosphatidylinositol 3-kinase-protein, 5' AMP-activated protein kinase, insulin resistance, sphingolipid, transforming growth factor-β, adipocyte lipolysis regulation, and oxytocin signaling pathways. In addition, there were sex differences in blood pressure, skeletal muscle mass, lean body mass, and percent body fat. CONCLUSIONS We have identified sex differences in miRNA expression in Hispanic adolescents relevant to cardiometabolic health. Future studies should focus on sex-specific mechanistic roles of miRNAs on gene pathways associated with obesity pathophysiology to support development of precision cardiometabolic interventions.
Collapse
Affiliation(s)
- Genesio M. Karere
- Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina,Corresponding author Department of Internal Medicine, Center for Precision Medicine, Wake Forest Baptist, Medical Center, Winston-Salem, NC 27157., Telephone: (336) 713-7561, Fax: (336) 713-7566,
| | - Laura A. Cox
- Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Andrew C. Bishop
- Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Andrew M. South
- Department of Pediatrics, Brenner Children’s Hospital, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina,Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Hossam A. Shaltout
- Department of Obstetrics and Gynecology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina
| | - Maria-Gisela Mercado-Deane
- Department of Radiology, Baylor College of Medicine, Children’s Hospital of San Antonio, San Antonio, Texas
| | - Suzanne Cuda
- Department of Pediatrics, Baylor College of Medicine, Children’s Hospital of San Antonio, San Antonio, Texas
| |
Collapse
|
|
38
|
Kim JH, Kim DH, Lim YH, Shin CH, Lee YA, Kim BN, Kim JI, Hong YC. Childhood Obesity-Related Mechanisms: MicroRNome and Transcriptome Changes in a Nested Case-Control Study. Biomedicines 2021; 9:biomedicines9080878. [PMID: 34440082 PMCID: PMC8389653 DOI: 10.3390/biomedicines9080878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/19/2021] [Accepted: 07/20/2021] [Indexed: 11/20/2022] Open
Abstract
Childhood obesity could contribute to adulthood obesity, leading to adverse health outcomes in adults. However, the mechanisms for how obesity is developed are still unclear. To determine the epigenome-wide and genome-wide expression changes related with childhood obesity, we compared microRNome and transcriptome levels as well as leptin protein levels in whole bloods of 12 obese and 24 normal children aged 6 years. miR-328-3p, miR-1301-3p, miR-4685-3p, and miR-6803-3p were negatively associated with all obesity indicators. The four miRNAs were also associated with 3948 mRNAs, and separate 475 mRNAs (185 among 3948 mRNAs) were associated with all obesity indicators. The 2533 mRNAs (64.2%) among the 3948 mRNAs and 286 mRNAs (60.2%) among the 475 mRNAs were confirmed as targets of the four miRNAs in public databases through miRWalk 2.0. Leptin protein was associated with miR-6803-3p negatively and all obesity indicators positively. Using DAVID bioinformatics resources 6.8, top three pathways for obesity-related gene set were metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway. The top three obesity-related disease classes were metabolic, cardiovascular, and chemdependency. Our results support that childhood obesity could be developed through miRNAs-related epigenetic mechanism and, further, these obesity-related epigenetic changes could control the pathways related with the development of various diseases.
Collapse
Affiliation(s)
- Jin Hee Kim
- Department of Integrative Bioscience & Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, Korea;
- Correspondence: (J.H.K.); (Y.-C.H.)
| | - Da Hae Kim
- Department of Integrative Bioscience & Biotechnology, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 05006, Korea;
| | - Youn-Hee Lim
- Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul 03080, Korea;
- Environmental Health Center, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Choong Ho Shin
- Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea; (C.H.S.); (Y.A.L.)
| | - Young Ah Lee
- Department of Pediatrics, Seoul National University College of Medicine, Seoul 03080, Korea; (C.H.S.); (Y.A.L.)
| | - Bung-Nyun Kim
- Division of Children and Adolescent Psychiatry, Department of Psychiatry, Seoul National University Hospital, Seoul 03080, Korea;
| | - Johanna Inhyang Kim
- Department of Psychiatry, Hanyang University Medical Center, Seoul 04763, Korea;
| | - Yun-Chul Hong
- Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul 03080, Korea;
- Environmental Health Center, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
- Correspondence: (J.H.K.); (Y.-C.H.)
| |
Collapse
|
|
39
|
Formichi C, Nigi L, Grieco GE, Maccora C, Fignani D, Brusco N, Licata G, Sebastiani G, Dotta F. Non-Coding RNAs: Novel Players in Insulin Resistance and Related Diseases. Int J Mol Sci 2021; 22:7716. [PMID: 34299336 PMCID: PMC8306942 DOI: 10.3390/ijms22147716] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022] Open
Abstract
The rising prevalence of metabolic diseases related to insulin resistance (IR) have stressed the urgent need of accurate and applicable tools for early diagnosis and treatment. In the last decade, non-coding RNAs (ncRNAs) have gained growing interest because of their potential role in IR modulation. NcRNAs are variable-length transcripts which are not translated into proteins but are involved in gene expression regulation. Thanks to their stability and easy detection in biological fluids, ncRNAs have been investigated as promising diagnostic and therapeutic markers in metabolic diseases, such as type 2 diabetes mellitus (T2D), obesity and non-alcoholic fatty liver disease (NAFLD). Here we review the emerging role of ncRNAs in the development of IR and related diseases such as obesity, T2D and NAFLD, and summarize current evidence concerning their potential clinical application.
Collapse
Affiliation(s)
- Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Carla Maccora
- Section of Medical Pathophysiology, Food Science and Endocrinology, Department of Experimental Medicine, Sapienza University, 00185 Rome, Italy;
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Noemi Brusco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (C.F.); (L.N.); (G.E.G.); (D.F.); (N.B.); (G.L.); (G.S.)
- Fondazione Umberto Di Mario, c/o Toscana Life Sciences, 53100 Siena, Italy
- Tuscany Centre for Precision Medicine (CReMeP), 53100 Siena, Italy
| |
Collapse
|
|
40
|
Ruskovska T, Budić-Leto I, Corral-Jara KF, Ajdžanović V, Arola-Arnal A, Bravo FI, Deligiannidou GE, Havlik J, Janeva M, Kistanova E, Kontogiorgis C, Krga I, Massaro M, Miler M, Milosevic V, Morand C, Scoditti E, Suárez M, Vauzour D, Milenkovic D. Systematic Bioinformatic Analyses of Nutrigenomic Modifications by Polyphenols Associated with Cardiometabolic Health in Humans-Evidence from Targeted Nutrigenomic Studies. Nutrients 2021; 13:2326. [PMID: 34371836 PMCID: PMC8308901 DOI: 10.3390/nu13072326] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/25/2021] [Accepted: 06/30/2021] [Indexed: 12/14/2022] Open
Abstract
Cardiometabolic disorders are among the leading causes of mortality in the human population. Dietary polyphenols exert beneficial effects on cardiometabolic health in humans. Molecular mechanisms, however, are not completely understood. Aiming to conduct in-depth integrative bioinformatic analyses to elucidate molecular mechanisms underlying the protective effects of polyphenols on cardiometabolic health, we first conducted a systematic literature search to identify human intervention studies with polyphenols that demonstrate improvement of cardiometabolic risk factors in parallel with significant nutrigenomic effects. Applying the predefined inclusion criteria, we identified 58 differentially expressed genes at mRNA level and 5 miRNAs, analyzed in peripheral blood cells with RT-PCR methods. Subsequent integrative bioinformatic analyses demonstrated that polyphenols modulate genes that are mainly involved in the processes such as inflammation, lipid metabolism, and endothelial function. We also identified 37 transcription factors that are involved in the regulation of polyphenol modulated genes, including RELA/NFKB1, STAT1, JUN, or SIRT1. Integrative bioinformatic analysis of mRNA and miRNA-target pathways demonstrated several common enriched pathways that include MAPK signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, focal adhesion, or PPAR signaling pathway. These bioinformatic analyses represent a valuable source of information for the identification of molecular mechanisms underlying the beneficial health effects of polyphenols and potential target genes for future nutrigenetic studies.
Collapse
Affiliation(s)
- Tatjana Ruskovska
- Faculty of Medical Sciences, Goce Delcev University, 2000 Stip, North Macedonia; (T.R.); (M.J.)
| | - Irena Budić-Leto
- Institute for Adriatic Crops and Karst Reclamation, 21000 Split, Croatia;
| | - Karla Fabiola Corral-Jara
- Unité de Nutrition Humaine (UNH), Université Clermont Auvergne, Institut National de Recherche pour L’agriculture, L’alimentation et L’environnement (INRAE), Faculté de Médecine, F-63000 Clermont-Ferrand, France; (K.F.C.-J.); (I.K.); (C.M.)
| | - Vladimir Ajdžanović
- Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (V.A.); (M.M.); (V.M.)
| | - Anna Arola-Arnal
- Nutrigenomics Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.A.-A.); (F.I.B.); (M.S.)
| | - Francisca Isabel Bravo
- Nutrigenomics Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.A.-A.); (F.I.B.); (M.S.)
| | - Georgia-Eirini Deligiannidou
- Department of Medicine, Democritus University of Thrace, Dragana, 68100 Alexandroupolis, Greece; (G.-E.D.); (C.K.)
| | - Jaroslav Havlik
- Department of Food Science, Czech University of Life Sciences, 16521 Prague, Czech Republic;
| | - Milkica Janeva
- Faculty of Medical Sciences, Goce Delcev University, 2000 Stip, North Macedonia; (T.R.); (M.J.)
| | - Elena Kistanova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria;
| | - Christos Kontogiorgis
- Department of Medicine, Democritus University of Thrace, Dragana, 68100 Alexandroupolis, Greece; (G.-E.D.); (C.K.)
| | - Irena Krga
- Unité de Nutrition Humaine (UNH), Université Clermont Auvergne, Institut National de Recherche pour L’agriculture, L’alimentation et L’environnement (INRAE), Faculté de Médecine, F-63000 Clermont-Ferrand, France; (K.F.C.-J.); (I.K.); (C.M.)
- Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia
| | - Marika Massaro
- National Research Council (CNR) Institute of Clinical Physiology (IFC), 73100 Lecce, Italy; (M.M.); (E.S.)
| | - Marko Miler
- Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (V.A.); (M.M.); (V.M.)
| | - Verica Milosevic
- Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (V.A.); (M.M.); (V.M.)
| | - Christine Morand
- Unité de Nutrition Humaine (UNH), Université Clermont Auvergne, Institut National de Recherche pour L’agriculture, L’alimentation et L’environnement (INRAE), Faculté de Médecine, F-63000 Clermont-Ferrand, France; (K.F.C.-J.); (I.K.); (C.M.)
| | - Egeria Scoditti
- National Research Council (CNR) Institute of Clinical Physiology (IFC), 73100 Lecce, Italy; (M.M.); (E.S.)
| | - Manuel Suárez
- Nutrigenomics Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, 43007 Tarragona, Spain; (A.A.-A.); (F.I.B.); (M.S.)
| | - David Vauzour
- Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK;
| | - Dragan Milenkovic
- Unité de Nutrition Humaine (UNH), Université Clermont Auvergne, Institut National de Recherche pour L’agriculture, L’alimentation et L’environnement (INRAE), Faculté de Médecine, F-63000 Clermont-Ferrand, France; (K.F.C.-J.); (I.K.); (C.M.)
- Department of Internal Medicine, Division of Cardiovascular Medicine, School of Medicine, University of California Davis, Davis, CA 95616, USA
| |
Collapse
|
|
41
|
Fodor A, Lazar AL, Buchman C, Tiperciuc B, Orasan OH, Cozma A. MicroRNAs: The Link between the Metabolic Syndrome and Oncogenesis. Int J Mol Sci 2021; 22:ijms22126337. [PMID: 34199293 PMCID: PMC8231835 DOI: 10.3390/ijms22126337] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/03/2021] [Accepted: 06/09/2021] [Indexed: 12/14/2022] Open
Abstract
Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis.
Collapse
Affiliation(s)
- Adriana Fodor
- Department of Diabetes and Nutrtion, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Andrada Luciana Lazar
- Department of Dermatology, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Cristina Buchman
- Department of Oncology, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Correspondence: (A.F.); (A.L.L.); (C.B.)
| | - Brandusa Tiperciuc
- Department of Pharmaceutical Chemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Olga Hilda Orasan
- Internal Medicine Department, 4th Medical Clinic “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.H.O.); (A.C.)
| | - Angela Cozma
- Internal Medicine Department, 4th Medical Clinic “Iuliu Haţieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (O.H.O.); (A.C.)
| |
Collapse
|
|
42
|
MicroRNA-mediated regulation of glucose and lipid metabolism. Nat Rev Mol Cell Biol 2021; 22:425-438. [PMID: 33772227 PMCID: PMC8853826 DOI: 10.1038/s41580-021-00354-w] [Citation(s) in RCA: 203] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2021] [Indexed: 02/01/2023]
Abstract
In animals, systemic control of metabolism is conducted by metabolic tissues and relies on the regulated circulation of a plethora of molecules, such as hormones and lipoprotein complexes. MicroRNAs (miRNAs) are a family of post-transcriptional gene repressors that are present throughout the animal kingdom and have been widely associated with the regulation of gene expression in various contexts, including virtually all aspects of systemic control of metabolism. Here we focus on glucose and lipid metabolism and review current knowledge of the role of miRNAs in their systemic regulation. We survey miRNA-mediated regulation of healthy metabolism as well as the contribution of miRNAs to metabolic dysfunction in disease, particularly diabetes, obesity and liver disease. Although most miRNAs act on the tissue they are produced in, it is now well established that miRNAs can also circulate in bodily fluids, including their intercellular transport by extracellular vesicles, and we discuss the role of such extracellular miRNAs in systemic metabolic control and as potential biomarkers of metabolic status and metabolic disease.
Collapse
|
|
43
|
Lischka J, Schanzer A, Hojreh A, Ba-Ssalamah A, de Gier C, Valent I, Item CB, Greber-Platzer S, Zeyda M. Circulating microRNAs 34a, 122, and 192 are linked to obesity-associated inflammation and metabolic disease in pediatric patients. Int J Obes (Lond) 2021; 45:1763-1772. [PMID: 33986456 PMCID: PMC8310785 DOI: 10.1038/s41366-021-00842-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 03/26/2021] [Accepted: 04/26/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Obesity-associated chronic low-grade inflammation leads to dysregulation of central lipid and glucose metabolism pathways leading to metabolic disorders. MicroRNAs (miRNAs) are known to control regulators of metabolic homeostasis. We aimed to assess the relationship of circulating miRNAs with inflammatory modulators and metabolic disorders in pediatric obesity. METHODS From a pediatric cohort with severe obesity (n = 109), clinically thoroughly characterized including diverse routine blood parameters, oral glucose tolerance test, and liver MRI, a panel of 16 circulating miRNAs was quantified using qRT-PCR. Additionally, markers of inflammation TNFα, IL1 receptor antagonist, procalcitonin, CRP, and IL-6 were measured. RESULTS Markers of obesity-associated inflammation, TNFα, IL-1Ra, and procalcitonin, all significantly correlated with concentrations of miRNAs 122 and 192. Concentrations of these miRNAs negatively correlated with serum adiponectin and were among those strongly linked to parameters of dyslipidemia and liver function. Moreover, miRNA122 concentrations correlated with HOMA-IR. Several miRNA levels including miRNAs 34a, 93, 122, and 192 were statistically significantly differing between individuals with prediabetes, impaired glucose tolerance, metabolic syndrome, or nonalcoholic fatty liver disease compared to the respective controls. Additionally, miRNA 192 was significantly elevated in metabolically unhealthy obesity. CONCLUSIONS A miRNA pattern associated with obesity-associated inflammation and comorbidities may be used to distinguish metabolically healthy from unhealthy pediatric patients with obesity. Moreover, these changes in epigenetic regulation could potentially be involved in the etiology of obesity-linked metabolic disease in children and adolescents.
Collapse
Affiliation(s)
- Julia Lischka
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Andrea Schanzer
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Azadeh Hojreh
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Ahmed Ba-Ssalamah
- Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Charlotte de Gier
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Isabella Valent
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Chike Bellarmine Item
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Susanne Greber-Platzer
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Maximilian Zeyda
- Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
44
|
LaBelle J, Bowser M, Brown A, Farnam L, Kho A, Li J, McGeachie M, Chase R, Piehl S, Allen K, Hobbs BD, Weiss ST, Hersh C, Tantisira K, Amr SS. Commercially Available Blocking Oligonucleotides Effectively Suppress Unwanted Hemolysis-Related miRNAs in a Large Whole-Blood RNA Cohort. J Mol Diagn 2021; 23:671-682. [PMID: 33872788 DOI: 10.1016/j.jmoldx.2021.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 03/15/2021] [Accepted: 03/25/2021] [Indexed: 12/23/2022] Open
Abstract
When sequencing small RNA libraries derived from whole blood, the most abundant microRNAs (miRs) detected are often miR-486-5p, miR-451a, and miR-92a-3p. These highly expressed erythropoietic miRs are released into the sample from red blood cell hemolysis. Next-generation sequencing of these unwanted miRs leads to a waste in sequencing cost and diminished detection of lowly expressed miRNAs, including many potential miRNA biomarkers. Previous work has developed a method to reduce targeted miRNAs using oligonucleotides that bind their target miRNA and prevent its ligation during library construction, although the extent to which oligonucleotides can be multiplexed and their effect on larger cohorts has not been thoroughly explored. We present a method for suppressing detection of three highly abundant heme miRs in a single multiplexed blocking oligonucleotide reaction. In a small paired-sample pilot (n = 8) and a large cohort of samples (n = 901), multiplexed oligos reduced detection of their target miRNAs by approximately 70%, allowing for an approximately 10-fold increase in reads mapping to nonheme miRs and increased detection of very lowly expressed miRs, with minimal off-target effects. By removing all three highly expressed erythropoietic miRNAs from next-generational sequencing libraries, this commercially available multiplexed blocking oligonucleotide method allows for greater detection of lowly expressed biomarkers, improving the efficacy, cost-efficiency, and sensitivity of biomarker studies and diagnostic tests.
Collapse
Affiliation(s)
- Jenna LaBelle
- Mass General Brigham Personalized Medicine, Partners Healthcare, Cambridge, Massachusetts
| | - Mark Bowser
- Mass General Brigham Personalized Medicine, Partners Healthcare, Cambridge, Massachusetts
| | - Alison Brown
- Mass General Brigham Personalized Medicine, Partners Healthcare, Cambridge, Massachusetts
| | - Leanna Farnam
- School of Health Sciences, Lasell University, Auburndale, Massachusetts
| | - Alvin Kho
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jiang Li
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Michael McGeachie
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Robert Chase
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | | | | | - Brian D Hobbs
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Scott T Weiss
- Mass General Brigham Personalized Medicine, Partners Healthcare, Cambridge, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Craig Hersh
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kelan Tantisira
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Sami S Amr
- Mass General Brigham Personalized Medicine, Partners Healthcare, Cambridge, Massachusetts; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
| |
Collapse
|
|
45
|
MicroRNAs in ascending thoracic aortic aneurysms. Biosci Rep 2021; 40:225830. [PMID: 32678444 PMCID: PMC7385583 DOI: 10.1042/bsr20200218] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 07/07/2020] [Accepted: 07/17/2020] [Indexed: 02/07/2023] Open
Abstract
Thoracic Aortic Aneurysm (TAA) is characterized by the dilation of the aorta and is fatal if not diagnosed and treated appropriately. The underlying genetic mechanisms have not been completely delineated, so better knowledge of the physiopathology of TAAs is needed to improve detection and therapy. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and are known to be involved in cardiovascular diseases (CVDs). The current study aimed to identify miRNAs that can be used as possible biomarkers for the early diagnosis of patients with ascending TAAs (ATAAs). MiRNA expression was profiled by NanoString nCounter technology using 12 samples including tissue and pre- and post-surgical plasma from ATAA patients. Four miRNAs were selected and further validated by real time polymerase chain reaction (RT-PCR) in 22 plasma samples from which three miRNAs (hsa-miR140-5p, hsa-miR-191-5p and hsa-miR-214-3p) showed significant expression level differences between the two types of plasma samples. Further analyses of the corresponding predicted target genes by these miRNAs, revealed two genes (Myotubularin-related protein 4 (MTMR4) and Phosphatase 1 catalytic subunit β (PPP1CB)) whose expression was inversely correlated with the expression of their respective miRNAs. Overall, in this pilot study, we identified three miRNAs that might serve as potential biomarkers and therapeutic targets in ATAA.
Collapse
|
|
46
|
Mencias M, Levene M, Blighe K, Bax BE. Circulating miRNAs as Biomarkers for Mitochondrial Neuro-Gastrointestinal Encephalomyopathy. Int J Mol Sci 2021; 22:3681. [PMID: 33916195 PMCID: PMC8037498 DOI: 10.3390/ijms22073681] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/05/2023] Open
Abstract
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and 65 age and sex matched healthy controls were recruited and assigned to one of four study phases: (i) discovery for sample size determination; (ii) candidate screening; (iii) candidate validation; and (iv) verifying the performance of the validated miRNA panel in four patients treated with erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement under development for MNGIE. Quantitative PCR (qPCR) was used to profile miRNAs in serum and/or plasma samples collected for the discovery, validation and performance phases, and next generation sequencing (NGS) analysis was applied to serum samples assigned to the candidate screening phase. Forty-one differentially expressed candidate miRNAs were identified in the sera of patients (p < 0.05, log2 fold change > 1). The validation cohort revealed that of those, 27 miRNAs were upregulated in plasma and three miRNAs were upregulated in sera (p < 0.05). Through binary logistic regression analyses, five plasma miRNAs (miR-192-5p, miR-193a-5p, miR-194-5p, miR-215-5p and miR-34a-5p) and three serum miRNAs (miR-192-5p, miR-194-5p and miR-34a-5p) were shown to robustly distinguish MNGIE from healthy controls. Reduced longitudinal miRNA expression of miR-34a-5p was observed in all four patients treated with EE-TP and coincided with biochemical and clinical improvements. We recommend the inclusion of the plasma exploratory miRNA biomarker panel in future clinical trials of investigational therapies for MNGIE; it may have prognostic value for assessing clinical status.
Collapse
Affiliation(s)
- Mark Mencias
- Molecular and Clinical Sciences, St. George’s, University of London, London SW17 0RE, UK; (M.M.); (M.L.)
| | - Michelle Levene
- Molecular and Clinical Sciences, St. George’s, University of London, London SW17 0RE, UK; (M.M.); (M.L.)
| | - Kevin Blighe
- Clinical Bioinformatics Research Ltd., London W1B 3HH, UK;
| | - Bridget E. Bax
- Molecular and Clinical Sciences, St. George’s, University of London, London SW17 0RE, UK; (M.M.); (M.L.)
| | | |
Collapse
|
|
47
|
The Potential Role of Exosomes in Child and Adolescent Obesity. CHILDREN-BASEL 2021; 8:children8030196. [PMID: 33800718 PMCID: PMC7999028 DOI: 10.3390/children8030196] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/17/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023]
Abstract
Child and adolescent obesity constitute one of the greatest contemporary public health menaces. The enduring disproportion between calorie intake and energy consumption, determined by a complex interaction of genetic, epigenetic, and environmental factors, finally leads to the development of overweight and obesity. Child and adolescent overweight/obesity promotes smoldering systemic inflammation (“para-inflammation”) and increases the likelihood of later metabolic and cardiovascular complications, including metabolic syndrome and its components, which progressively deteriorate during adulthood. Exosomes are endosome-derived extracellular vesicles that are secreted by a variety of cells, are naturally taken-up by target cells, and may be involved in many physiological and pathological processes. Over the last decade, intensive research has been conducted regarding the special role of exosomes and the non-coding (nc) RNAs they contain (primarily micro (mi) RNAs, long (l) non-coding RNAs, messenger (m) RNAs and other molecules) in inter-cellular communications. Through their action as communication mediators, exosomes may contribute to the pathogenesis of obesity and associated disorders. There is increasing evidence that exosomal miRNAs and lncRNAs are involved in pivotal processes of adipocyte biology and that, possibly, play important roles in gene regulation linked to human obesity. This review aims to improve our understanding of the roles of exosomes and their cargo in the development of obesity and related metabolic and inflammatory disorders. We examined their potential roles in adipose tissue physiology and reviewed the scarce data regarding the altered patterns of circulating miRNAs and lncRNAs observed in obese children and adolescents, compared them to the equivalent, more abundant existing findings of adult studies, and speculated on their proposed mechanisms of action. Exosomal miRNAs and lncRNAs could be applied as cardiometabolic risk biomarkers, useful in the early diagnosis and prevention of obesity. Furthermore, the targeting of crucial circulating exosomal cargo to tissues involved in the pathogenesis and maintenance of obesity could provide a novel therapeutic approach to this devastating and management-resistant pandemic.
Collapse
|
|
48
|
Fernández-Ruiz VE, Solé-Agustí M, Armero-Barranco D, Cauli O. Weight Loss and Improvement of Metabolic Alterations in Overweight and Obese Children Through the I 2AO 2 Family Program: A Randomized Controlled Clinical Trial. Biol Res Nurs 2021; 23:488-503. [PMID: 33517762 DOI: 10.1177/1099800420987303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Childhood obesity is a major public health concern. We wanted to evaluate the effectiveness of a multidisciplinary program based on healthy eating, exercise, cognitive-behavioral therapy, and health education to achieve weight loss and improve metabolic parameters in overweight and obese children. A randomized, controlled clinical trial with long-term follow-up (24 months) was conducted at a community care center in overweight and obese individuals aged 6-12 years. A sample of 108 children was divided into an experimental and a control group receiving a standard care program. The experimental groups received a 12-month interdisciplinary program; the results were evaluated at 4 months, the end of the intervention, and at follow-up 12 months later. Anthropometric and biological marker measurements related to metabolic alterations, dyslipidemia (based on total cholesterol), hyperglycemia, fasting glycaemia, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in blood were recorded. The intervention had a significant effect (p < 0.001) in terms of decreased body mass index, skinfolds, and waist and arm circumferences. These changes were accompanied by biochemical changes underlying an improvement in metabolic parameters, such as a significant reduction in total cholesterol, low-density lipoprotein-cholesterol, triglycerides, and hyperglycemia and a significant increase in high-density lipoprotein-cholesterol. These effects were still significant for markers of excess weight or obesity in the experimental group 12 months after the end of the intervention, suggesting that an enduring change in healthy lifestyles had been maintained period. This interdisciplinary, nurse-led program helped to reduce childhood and adolescent excess weight and obesity and had long-lasting effects.
Collapse
Affiliation(s)
- Virginia E Fernández-Ruiz
- Department of Endocrinology and Nutrition, Virgen de la Arrixaca University Clinic Hospital Murcia, Spain.,Nursing Department, Faculty of Nursing, Calle Campus Universitario, 16751University of Murcia, Spain
| | | | - David Armero-Barranco
- Nursing Department, Faculty of Nursing, Calle Campus Universitario, 16751University of Murcia, Spain
| | - Omar Cauli
- Nursing Department, Faculty of Nursing and Podiatrics, 16781University of Valencia, Spain
| |
Collapse
|
|
49
|
Maude H, Sanchez-Cabanillas C, Cebola I. Epigenetics of Hepatic Insulin Resistance. Front Endocrinol (Lausanne) 2021; 12:681356. [PMID: 34046015 PMCID: PMC8147868 DOI: 10.3389/fendo.2021.681356] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 04/20/2021] [Indexed: 01/14/2023] Open
Abstract
Insulin resistance (IR) is largely recognized as a unifying feature that underlies metabolic dysfunction. Both lifestyle and genetic factors contribute to IR. Work from recent years has demonstrated that the epigenome may constitute an interface where different signals may converge to promote IR gene expression programs. Here, we review the current knowledge of the role of epigenetics in hepatic IR, focusing on the roles of DNA methylation and histone post-translational modifications. We discuss the broad epigenetic changes observed in the insulin resistant liver and its associated pathophysiological states and leverage on the wealth of 'omics' studies performed to discuss efforts in pinpointing specific loci that are disrupted by these changes. We envision that future studies, with increased genomic resolution and larger cohorts, will further the identification of biomarkers of early onset hepatic IR and assist the development of targeted interventions. Furthermore, there is growing evidence to suggest that persistent epigenetic marks may be acquired over prolonged exposure to disease or deleterious exposures, highlighting the need for preventative medicine and long-term lifestyle adjustments to avoid irreversible or long-term alterations in gene expression.
Collapse
Affiliation(s)
| | | | - Inês Cebola
- *Correspondence: Hannah Maude, ; Inês Cebola,
| |
Collapse
|
|
50
|
The Emerging Role of MicroRNAs in NAFLD: Highlight of MicroRNA-29a in Modulating Oxidative Stress, Inflammation, and Beyond. Cells 2020; 9:cells9041041. [PMID: 32331364 PMCID: PMC7226429 DOI: 10.3390/cells9041041] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/15/2020] [Accepted: 04/18/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and ranges from steatosis to steatohepatitis and to liver fibrosis. Lipotoxicity in hepatocytes, elevated oxidative stress and the activation of proinflammatory mediators of Kupffer cells, and fibrogenic pathways of activated hepatic stellate cells can contribute to the development of NAFLD. MicroRNAs (miRs) play a crucial role in the dysregulated metabolism and inflammatory signaling connected with NAFLD and its progression towards more severe stages. Of note, the protective effect of non-coding miR-29a on liver damage and its versatile action on epigenetic activity, mitochondrial homeostasis and immunomodulation may improve our perception of the pathogenesis of NAFLD. Herein, we review the biological functions of critical miRs in NAFLD, as well as highlight the emerging role of miR-29a in therapeutic application and the recent advances in molecular mechanisms underlying its liver protective effect.
Collapse
|