Exercise Training-Induced Changes in MicroRNAs: Beneficial Regulatory Effects in Hypertension, Type 2 Diabetes, and Obesity

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Term Occurence Count Dictionary
obesity 45 endocrinologydiseases
type 2 diabetes mellitus 2 endocrinologydiseases
Insulin 6 endocrinologydiseasesdrugs
diabetes mellitus 4 endocrinologydiseases
hyperglycemia 8 endocrinologydiseases
hyperinsulinemia 1 endocrinologydiseases
hyperlipidemia 1 endocrinologydiseases
metabolic syndrome 3 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 23768 environmental factors, which include a hypercaloric diet, obesity, and a sedentary lifestyle [[105]]. Insulin resistance in target tissues is the primary pathogenic mechanism of T2D that leads to hyperglycemia.
Insulin 25298 injury [[108]]. Several miRNAs known to be altered in T2D (Figure 2) are described below.3.1. MiRNAs, Insulin Synthesis, and SecretionHigh blood glucose levels lead to increased insulin production by increasing
Insulin 27277 reported increased serum levels of miR-375 in T2D patients, along with miR-101 and miR-802 [[121]]. Insulin secretion can also be affected by the overexpression of miR-9, which targets the transcription factor
Insulin 27763 tissues of non-obese diabetic rats, suggesting a role in the disease pathogenesis [[123]].3.2. MiRNAs and Insulin ResistanceA high-fat and sugar diet is associated with hyperglycemia, hyperlipidemia, and insulin resistance.
Insulin 36018 Angiotensin-converting enzyme [[164]], Adiponectin [[165]], IGF2 receptor [[166]], and Sirtuins—SIRT [[167]]. Insulin -like growth factor (IGF) and its receptor (IGF type 2 receptor: IGF2R) are involved in a variety of
Insulin 38986 element-binding protein (CREB), which is associated with a susceptibility to diabetic nephropathy [[176]]. Insulin resistance is related to the diverse complications of T2D and chronic inflammation also contributes
Select Disease Character Offset Disease Term Instance
diabetes mellitus 1355 physical exercise, and also in disease settings, such as systemic arterial hypertension (SAH), type 2 diabetes mellitus (T2D), and obesity. In SAH, microRNAs play a significant role in the regulation of key signaling pathways
diabetes mellitus 6338 34.7% in the latest years [[28]]. Cardiovascular events are the main cause of death in patients with diabetes mellitus [[29]]. Type 2 Diabetes mellitus (T2D) is a highly prevalent metabolic disease, with more than 400 million
diabetes mellitus 8130 such as sedentary lifestyle, psychological stress, smoking, obesity, alcoholism, caffeine consumption, diabetes mellitus type 2, and others [[40]].Different pathophysiological processes involved in SAH are now known to be
diabetes mellitus 36619 distribution and T2D development [[166]]. However, the role of genetic variants of the IGF2R system in type 2 diabetes mellitus is still unclear. Lv and colleagues (2008) demonstrated that the ACAA-insertion/deletion polymorphism
hyperglycemia 23862 [[105]]. Insulin resistance in target tissues is the primary pathogenic mechanism of T2D that leads to hyperglycemia . A constant glucose elevated level is a permanent insult to the expansion of β-cell mass to increase
hyperglycemia 24108 this compensatory mechanism to maintain glucose homeostasis fails in T2D patients, leading to chronic hyperglycemia and hyperinsulinemia [[106]]. The molecular mechanisms underlying insulin resistance, impairment of
hyperglycemia 26433 miR-9 [[118]].The molecular mechanisms involved in the chronic adaptation of pancreatic β-cells to hyperglycemia are not fully elucidated. Different experimental models were used to investigate the role of different
hyperglycemia 27625 been demonstrated that miR-222, miR-27a, miR-195, miR-103, and miR-10b expression patterns varied with hyperglycemia in insulin-target tissues of non-obese diabetic rats, suggesting a role in the disease pathogenesis
hyperglycemia 27826 pathogenesis [[123]].3.2. MiRNAs and Insulin ResistanceA high-fat and sugar diet is associated with hyperglycemia , hyperlipidemia, and insulin resistance. In this context, the pattern of phosphorylation in serine residues
hyperglycemia 37800 LPL that leads to ectopic fat deposition in peripheral tissues and contributes to insulin resistance, hyperglycemia , and progressively to T2DM [[173]].Polymorphisms in the sequence of pri-miRNA have been reported for
hyperglycemia 54753 and obesity, and reduced levels in SAH [[99],[141],[201]]. MiR-27a was increased and associated with hyperglycemia and metabolic syndrome in T2D patients, also playing a role in adipogenesis and in the regulation of
hyperglycemia 73571 Diabetes, including insulin synthesis, intracellular signaling/insulin resistance, lipid metabolism, and hyperglycemia . Circulating miRNAs evaluated in serum, plasma, whole-blood, or mononuclear cells, in clinical studies,
hyperinsulinemia 24126 mechanism to maintain glucose homeostasis fails in T2D patients, leading to chronic hyperglycemia and hyperinsulinemia [[106]]. The molecular mechanisms underlying insulin resistance, impairment of insulin signaling, and
hyperlipidemia 27841 [[123]].3.2. MiRNAs and Insulin ResistanceA high-fat and sugar diet is associated with hyperglycemia, hyperlipidemia , and insulin resistance. In this context, the pattern of phosphorylation in serine residues of insulin
metabolic syndrome 45766 identified as regulators of the TLR/NFκB pathway, only miR-181a had a significant correlation with metabolic syndrome and coronary artery disease [[202]]. In the opposite direction, miR-223 seems to exert a suppressive
metabolic syndrome 50183 metabolism is a serine hydrolase known as Butyrylcholinesterase (BChE; EC 3.1.1.8), which is related to metabolic syndrome risk in obese patients [[220]]). In these individuals, the BChE expression is higher than in lean subjects,
metabolic syndrome 54771 reduced levels in SAH [[99],[141],[201]]. MiR-27a was increased and associated with hyperglycemia and metabolic syndrome in T2D patients, also playing a role in adipogenesis and in the regulation of blood pressure [[228]].Currently,
obesity 1384 disease settings, such as systemic arterial hypertension (SAH), type 2 diabetes mellitus (T2D), and obesity . In SAH, microRNAs play a significant role in the regulation of key signaling pathways that lead to
obesity 1900 levels in T2D, and participate in lipid metabolism, adipogenesis, and adipocyte differentiation in obesity , with specific microRNA signatures involved in the pathogenesis of each disease. Many studies report
obesity 2410 processes. This review aimed to highlight microRNAs already known to be associated with SAH, T2D, and obesity , as well as their possible regulation by exercise training.1. Introduction1.1. MicroRNAsMicroRNAs (miRNAs)
obesity 4032 gene polymorphisms in the development of a great number of diseases such as hypertension, diabetes, obesity , and cardiovascular diseases [[13],[14]].Besides the role of individual variability, one of the many
obesity 6764 independent risk factor for cardiac diseases [[31]]. In 2013, the American Medical Association recognized obesity as a disease, which is now considered to be a worldwide epidemic [[32]]. This is a progressive and multifactorial
obesity 7019 increase of white adipose tissue due to both hypertrophy and hyperplasia of adipocytes [[33]]. Moreover, obesity is highly associated with T2D and cardiovascular diseases [[34],[35],[36]]. The involvement of dysregulated
obesity 7159 and cardiovascular diseases [[34],[35],[36]]. The involvement of dysregulated miRNAs in SAH, T2D, and obesity is reviewed below.2. MiRNAs and Systemic Arterial Hypertension (SAH)SAH is clinically defined as a persistent
obesity 8087 genetics—or modifiable risk factors, such as sedentary lifestyle, psychological stress, smoking, obesity , alcoholism, caffeine consumption, diabetes mellitus type 2, and others [[40]].Different pathophysiological
obesity 23724 result of combined genetic predisposition and environmental factors, which include a hypercaloric diet, obesity , and a sedentary lifestyle [[105]]. Insulin resistance in target tissues is the primary pathogenic mechanism
obesity 40341 sensitivity, and lipid metabolism [[179]]. Other miRNAs may be involved with inflammatory processes in obesity , either in the adipose tissue or systemically (Figure 3).4.1. MiRNAs Involved with Adipocyte Differentiation
obesity 40818 PPARγ is a member of nuclear receptors that regulate the transcription of several genes associated with obesity and diabetes [[182]]. It stimulates adipocyte differentiation and proliferation in order to increase
obesity 41743 mutation, or reduction of PTEN has several clinical implications, including insulin sensitivity and obesity [[188]]. Other miRNAs, including miR-103, miR-107, and miR-143, regulate hepatic insulin sensitivity
obesity 41957 obese individuals through different mechanisms [[189],[190]].MiR-126 was found to be downregulated in obesity and this may be involved in several processes since one of its targets in adipocytes is PI3KR, a PI3K
obesity 42655 modulates the expression of SPRED1, which has inhibitory actions to RAF1. Thus, SPRED1 is increased in obesity and reduces angiogenesis and vascular integrity, which may contribute to endothelial dysfunction. Indeed,
obesity 45313 to be increased in the adipose tissue, miR-18a was underexpressed [[201]].Inflammatory processes in obesity are closely linked to insulin resistance, T2D, and cardiovascular disease. TLR/NFκB (Toll like receptor/Nuclear
obesity 47635 investigated. IL-18, a pro-inflammatory cytokine member of the interleukin-1 family, is elevated in obesity and acts in conjunction with other cytokines, including IL-1, to activate the NFκB and transcription
obesity 48150 al. (2017) investigated the association between the IL18RAP gene polymorphisms, body mass index, and obesity [[214]]. They selected five SNPs in the IL18RAP that could change the miRNA-136 binding site. MiR-136
obesity 48461 homeostasis in hypothalamic neurons [[215],[216],[217]]. The rs7559479 G allele has a high association with obesity and the body mass index which augments the susceptibility to obesity. On the other side, the rs7559479
obesity 48530 allele has a high association with obesity and the body mass index which augments the susceptibility to obesity . On the other side, the rs7559479 A allele was associated with an increased miR-136 binding to IL18RAP,
obesity 48858 may change the microRNA binding sites. Richardson et al. (2011) evaluated the association of SNPs and obesity , demonstrating the role of the creation of a new regulatory site to miRNA due to these SNP in disease
obesity 49040 due to these SNP in disease development [[218]]. These studies demonstrated the association between obesity and SNPs at human PLIN4/S3-12, which is a member of the PAT (perilipin, adipose differentiation-related
obesity 50014 the effects of the association of genetic factors with environmental factors in the susceptibility to obesity development. Another key regulatory element in the lipid metabolism is a serine hydrolase known as Butyrylcholinesterase
obesity 50830 activity, leading to alterations in different metabolic pathways and contributing to the development of obesity . These findings demonstrate that SNPs in a variety of genes involved in the metabolism may affect homeostasis,
obesity 51095 Overlapping miRNAs in SAH, T2D, and ObesityAfter the review of miRNAs associated with SAH, T2D, and obesity , it was possible to find 144 miRNAs with an altered expression in experimental and clinical studies.
obesity 51414 identify 16 miRNAs with an altered expression that overlapped between T2D and SAH, 19 between T2D and obesity , and 15 between obesity and SAH. We also found 8 miRNAs—miR-21, miR-27a, miR-30d, miR-126, miR-143,
obesity 51438 altered expression that overlapped between T2D and SAH, 19 between T2D and obesity, and 15 between obesity and SAH. We also found 8 miRNAs—miR-21, miR-27a, miR-30d, miR-126, miR-143, miR-181a, miR-222, and
obesity 51664 overlapped between the three diseases (Figure 4 and Figure 5).MiR-21 was upregulated in SAH, T2D, and obesity , both in experimental and in clinical studies, suggesting a potential role in the common aspects of
obesity 52366 hypertrophy [[223]].The underexpression of miR-126 is consistently reported in the context of SAH, T2D, and obesity in both experimental and clinical studies. Under physiological conditions, miR-126 is highly expressed
obesity 53332 [[51]].Data from clinical studies revealed the increased expression of circulating miR-222 in SAH, T2D, and obesity . MiR-222 participates in several physiological functions in the cardiovascular system and an increasing
obesity 53656 physiological functions of cardiomyocytes [[225]].MiR-223 was found to be increased in the adipose tissue in obesity , working as a compensatory anti-inflammatory molecule, but with a reduced expression in the circulation
obesity 54482 activation [[227]].Different studies have reported reduced circulating levels of miR-181a both in T2D and obesity , while increased levels have been reported for hypertensive patients [[89]]. The opposite pattern was
obesity 54656 patients [[89]]. The opposite pattern was found for miR-30d, with increased circulating levels in T2D and obesity , and reduced levels in SAH [[99],[141],[201]]. MiR-27a was increased and associated with hyperglycemia
obesity 56049 training exerts beneficial effects in healthy [[231]] and in individuals with SAH [[232]], T2D [[233]], obesity [[234],[235]], cancer [[236]], coronary heart disease [[237]], and chronic heart failure [[238]].Aerobic
obesity 57696 vasculature, heart, and skeletal muscles.In addition to the study of miRNA dysregulation in SAH, T2D, and obesity , the influence of exercise training in the expression of miRNAs in pre-clinical and clinical studies
obesity 58254 exercise training in miRNA-mediated gene regulation in the population of patients with SAH, T2D, and obesity are currently unexplored since the majority of clinical studies focus on healthy subjects. Identification
obesity 58845 comparing the expression profile of these miRNAs with the miRNAs reviewed in the context of SAH, T2D, and obesity , we found significant overlaps (Figure 4 and Figure 5). Among the miRNAs evaluated in the experimental
obesity 62150 induction of increased levels of miR-126 by exercise could counteract the underexpression found in obesity , SAH, and T2D.MiR-143 was found to be reduced in the heart, experimentally, after a chronic adaptation
obesity 64424 negatively regulates the expression of the CCL2 gene [[35]], which is involved in the development of the obesity -induced inflammation and insulin resistance in the skeletal muscle [[224]]. MiR-126 also reduces vascular
obesity 71219 Exercises: miRNAs Differentially Expressed Other miRNAs were found with opposite expression between obesity and exercise training (Figure 6), including miR-26a, miR-27b, and miR-206. The MiRNA-26 family is also
obesity 71615 miR-26a after aerobic [[231]] and resistance exercises [[288]]. MiR-27b targets PPARγ, being reduced in obesity and increased after exercise [[253],[256]]. MiR-206, which was shown to block adipogenesis [[289]],
obesity 71982 pathogenesis of cardiometabolic diseases and common regulatory pathways can be identified in SAH, T2D, and obesity . Exercise training modulates the expression of several miRNAs—both in the short-term and in long-term—which
obesity 72802 training can contribute to the development of new drugs and therapies for the treatment of SAH, T2D, and obesity .Figure 1The dysregulated miRNA profile in Hypertension. The diagram shows the miRNA expression pattern
obesity 73877 report either increased or decreased expression of the miRNA.Figure 3The dysregulated miRNA profile in obesity . The diagram shows the miRNA expression pattern found in the adipose tissue and during MSC/preadipocyte
obesity 74215 also listed. ↑ = upregulated, ↓ = downregulated.Figure 4A Venn diagram of hypertension, diabetes, obesity , and their overlapping with exercises (pre-clinical). The Venn diagram was used to identify overlapping
obesity 74543 diseases and pre-clinical studies on exercise training.Figure 5A Venn diagram of hypertension, diabetes, obesity , and their overlapping with exercises (clinical). The Venn diagram was used to identify overlapping
type 2 diabetes mellitus 1348 adaptation to physical exercise, and also in disease settings, such as systemic arterial hypertension (SAH), type 2 diabetes mellitus (T2D), and obesity. In SAH, microRNAs play a significant role in the regulation of key signaling pathways
type 2 diabetes mellitus 36612 distribution and T2D development [[166]]. However, the role of genetic variants of the IGF2R system in type 2 diabetes mellitus is still unclear. Lv and colleagues (2008) demonstrated that the ACAA-insertion/deletion polymorphism

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