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Current Insights on the Role of Irisin in Endothelial Dysfunction.
Luna-Ceron, E, González-Gil, AM, Elizondo-Montemayor, L
Current vascular pharmacology. 2022;(3):205-220
Abstract
Endothelial dysfunction is a crucial physiopathological mechanism for cardiovascular diseases that results from the harmful impact of metabolic disorders. Irisin, a recently discovered adipomyokine, has been shown to exert beneficial metabolic effects by increasing energy consumption, improving insulin sensitivity, and reducing the proinflammatory milieu. Multiple preclinical models have assessed irisin's possible role in the development of endothelial dysfunction, displaying that treatment with exogenous irisin can decrease the production of oxidative stress mediators by up-regulating Akt/mTOR/Nrf2 pathway, promote endothelial-dependent vasodilatation through the activation of AMPK-PI3K-AkteNOS pathway, and increase the endothelial cell viability by activation of ERK proliferation pathway and downregulation of Bad/Bax/Caspase 3 pro-apoptotic pathway. However, there is scarce evidence of these mechanisms in clinical studies, and available results are controversial. Some have shown negative correlations of irisin levels with the burden of coronary atherosclerosis and leukocyte adhesion molecules' expression. Others have demonstrated associations between irisin levels and increased atherosclerosis risk and higher carotid intima-media thickness. Since the role of irisin in endothelial damage remains unclear, in this review, we compare, contrast, and integrate the current knowledge from preclinical and clinical studies to elucidate the potential preventive role and the underlying mechanisms and pathways of irisin in endothelial dysfunction. This review also comprises original figures to illustrate these mechanisms.
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The Effect of a Life-Style Intervention Program of Diet and Exercise on Irisin and FGF-21 Concentrations in Children and Adolescents with Overweight and Obesity.
Karampatsou, SI, Genitsaridi, SM, Michos, A, Kourkouni, E, Kourlaba, G, Kassari, P, Manios, Y, Charmandari, E
Nutrients. 2021;(4)
Abstract
Overweight and obesity in childhood and adolescence represent major public health problems of our century, and account for increased morbidity and mortality in adult life. Irisin and Fibroblast Growth Factor 21 (FGF-21) have been proposed as prognostic and/or diagnostic biomarkers in subjects with obesity and metabolic syndrome, because they increase earlier than other traditional biomarkers. We determined the concentrations of Irisin and FGF-21 in children and adolescents with overweight and obesity before and after one year of a life-style intervention program of diet and physical exercise and explored the impact of body mass index (BMI) reduction on the concentrations of Irisin, FGF-21 and other cardiometabolic risk factors. Three hundred and ten (n = 310) children and adolescents (mean age ± SD: 10.5 ± 2.9 years) were studied prospectively. Following one year of the life-style intervention program, there was a significant decrease in BMI (p = 0.001), waist-to-hip ratio (p = 0.024), waist-to-height ratio (p = 0.024), and Irisin concentrations (p = 0.001), and an improvement in cardiometabolic risk factors. There was no alteration in FGF-21 concentrations. These findings indicate that Irisin concentrations decreased significantly as a result of BMI reduction in children and adolescents with overweight and obesity. Further studies are required to investigate the potential role of Irisin as a biomarker for monitoring the response to lifestyle interventions and for predicting the development of cardiometabolic risk factors.
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Effects of GLP-1 receptor agonists on myokine levels and pro-inflammatory cytokines in patients with type 2 diabetes mellitus.
Guarnotta, V, Bianco, MJ, Vigneri, E, Panto', F, Lo Sasso, B, Ciaccio, M, Pizzolanti, G, Giordano, C
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2021;(11):3193-3201
Abstract
BACKGROUND AND AIMS To evaluate the change in circulating serum irisin and interleukin-6 (IL-6), in patients with type 2 diabetes mellitus (T2DM) after 6 and 12 months of GLP-1 treatment. METHODS AND RESULTS Eighty-five patients with T2DM inadequately controlled with insulin or other hypoglycaemic drugs were added to dulaglutide (N° = 44) and liraglutide (N° = 41) treatment. After 6 months of GLP-1 analogues a significant decrease in BMI (p < 0.001), waist circumference (WC) (p < 0.001), fasting blood glucose (p < 0.001), HbA1c (p < 0.001), total cholesterol (p < 0.001), LDL-cholesterol (p = 0.003), triglycerides (p = 0.017), IL-6 (p = 0.045) and a significant increase in serum irisin (p < 0.001) were observed compared to baseline. After 12 months of treatment no significant differences were found compared to the levels at 6 months. The change in irisin from baseline (Δ_irisin) was significantly related to the changes in total-cholesterol (Δ_total-cholesterol) (r = -0.293; p = 0.020), while the change in IL-6 (Δ_IL-6) was significantly related to the changes in WC (Δ_WC) (r = 0.347; p = 0.006). CONCLUSIONS Additive treatment with GLP1-analogues results in an increase in serum circulating irisin levels and a decrease in IL-6. The post-treatment change in irisin was correlated with a decrease in total cholesterol, while the change in IL-6 was correlated with a decrease in WC.
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Effects of competitive physical activity on serum irisin levels and bone turnover markers.
Gaudio, A, Rapisarda, R, Xourafa, A, Zanoli, L, Manfrè, V, Catalano, A, Signorelli, SS, Castellino, P
Journal of endocrinological investigation. 2021;(10):2235-2241
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Abstract
BACKGROUND Irisin, a myokine, is a polypeptide derived from the cleavage of the extracellular domain of fibronectin domain-containing protein 5, a receptor that is present on different tissues (skeletal muscle, pericardium, myocardium, and brain), whose functions are not yet fully defined. PURPOSE The main aim of our study was to evaluate the effect of competitive physical activity on serum irisin levels and bone turnover markers. METHODS Fifteen male footballers and an equal number of subjects of the same age and gender, but with a predominantly sedentary lifestyle, had their serum levels of irisin and bone turnover markers measured. Bone mineral status was evaluated in both groups by quantitative bone ultrasound of the calcaneus. In addition, only in footballers, biochemical analyses were repeated after 3 months. RESULTS We did not observe significant differences in the serum levels of calcium, phosphorus, and parathyroid hormone between the two groups. The footballers had significantly higher quantitative bone ultrasound, 25-OH vitamin D, and creatinine values than the controls. There were also no significant differences in the bone alkaline phosphatase, carboxy-terminal telopeptide of type I collagen, osteoprotegerin, sclerostin or Dkk-1 values, while the irisin levels (+ 89%, p < 0.001) and RANKL were significantly higher in the footballers compared to those in the controls. CONCLUSION Our study shows that footballers have significantly higher serum irisin values than the general population. Irisin could be the "trait d'union" between bone health and physical activity.
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Associations of circulating irisin with 24-h blood pressure, total and visceral fat, and metabolic parameters in young adult hypertensives.
Miazgowski, T, Miazgowski, B, Kaczmarkiewicz, A, Kopeć, J
Archives of endocrinology and metabolism. 2021;(2):137-143
Abstract
OBJECTIVE Some experimental and clinical studies suggest a possible role of irisin in central and peripheral regulation of blood pressure. The purpose of the study was to assess the associations between serum irisin levels, total and visceral fat, metabolic parameters, and blood pressure pattern during 24-h monitoring (ABPM). METHODS In 206 patients with essential hypertension receiving standard antihypertensive treatments, we assessed anthropometric indices; serum irisin, blood lipids (total cholesterol, LDL-C, HDL-C, and triglycerides), glucose and insulin; body composition including lean mass and total, visceral, android and gynoid fat using a dual-energy x-ray absorptiometry; ABPM; and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). RESULTS Baseline irisin levels were within normal reference ranges and comparable between the genders. There were no significant correlations of irisin with age, anthropometric variables, lipids, HOMA-IR, body composition, as well as 24-h blood pressure and dipping status. In univariate analysis, age, fat mass and distribution, lipids and glucose, HOMA-IR, and nocturnal blood pressure fall were poor predictors of irisin levels. These neutral associations were not affected by age, gender, and treatment modality. CONCLUSION In young adult hypertensives, serum concentration of irisin was within a normal range and not associated with total and regional fat, blood lipids, insulin resistance, as well as 24-h blood pressure and the magnitude of its nocturnal fall.
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Cardiometabolic health, visceral fat and circulating irisin levels: results from a real-world weight loss study.
Miazgowski, T, Kaczmarkiewicz, A, Miazgowski, B, Kopeć, J
Journal of endocrinological investigation. 2021;(6):1243-1252
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Abstract
BACKGROUND The aim of this pragmatic intervention study was to investigate changes in cardiometabolic outcomes, irisin plasma concentration, and body composition during a 4-month intervention in unselected obese individuals. MATERIALS AND METHODS In 111 obese women aged 36.73 ± 7.2 years, we measured changes in weight, lipid profiles, glucose, insulin, Homeostatic Model Assessment-Insulin Resistance Index (HOMA-IR), uric acid, aminotransferases, and irisin. Body composition including lean mass (LM) and total (TF), gynoid (GF), android (AF), and visceral fat (VF) was assessed using densitometry. Physical activity was assessed using the International Physical Activity Questionnaire (IPAQ). The participants received tailored written advice targeting lifestyle according to current guidelines. At follow-up, patients rated their adherence in the self-administered questionnaire. RESULTS Mean weight loss in the whole group was 3.12 kg (- 3.3%); 26% of the women achieved the desired target of weight loss (> 5% of the initial weight), whereas weight decreased moderately in 50% and increased in 14%. In 86 women with weight loss, there were significant changes in HOMA-IR (- 13.8%), insulin (- 11.2%), alanine aminotransferase (- 8.0%), VF (- 7.0%), AF (- 5.4%), TF (- 4.7%), GF (- 2.8%) and LM (- 1.5%), whereas irisin and HDL-C levels and the mean IPAQ score did not change. CONCLUSIONS In this real-world evidence study, a successful weight loss achieved only 26% of patients, with overall much better adherence to diet restriction than to exercise. However, even mild to moderate weight loss resulted in significant improvements in cardiometabolic health. Weight loss was associated with a modest LM decrease but did not influence plasma irisin.
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The effect of fenugreek seed supplementation on serum irisin levels, blood pressure, and liver and kidney function in patients with type 2 diabetes mellitus: A parallel randomized clinical trial.
Hadi, A, Arab, A, Hajianfar, H, Talaei, B, Miraghajani, M, Babajafari, S, Marx, W, Tavakoly, R
Complementary therapies in medicine. 2020;:102315
Abstract
OBJECTIVES This study was designed to determine the effects of fenugreek seed (FS) on serum irisin levels, blood pressure, and liver and kidney function in patients with type 2 diabetes mellitus (T2DM). METHODS In an 8-week randomized controlled clinical trial, T2DM patients (n = 50) were assigned to the intervention (5 g FS powder, 3 times a day) or control group. Both groups received anti-diabetic drugs and nutritional consults. Serum samples were collected and blood pressure was measured at baseline and end of the trial. Data on dietary intake and physical activity was determined using the questionnaires. RESULTS Compared to the control group, FS consumption resulted in a significant decrease in fasting plasma glucose (FPG) (p = 0.024), as well as a significant change in serum alanine aminotransferase (ALT) (p = 0.02) and alkaline phosphatase (ALP) (p = 0.001). Within-group analysis showed a significant decrease in aspartate aminotransferase (AST) (p = 0.014), systolic blood pressure (SBP) (p = 0.001), and irisin (p = 0.001) in the FS group, and a significant increase in creatinine (Cr) (p = 0.001) and decrease in estimated glomerular filtration rate (eGFR) (p = 0.001) in the control group. FS consumption did not have any significant effect on diastolic blood pressure (DBP) and blood urea nitrogen (BUN). CONCLUSION FS intake has some beneficial effects on FPG, SBP, and some liver and kidney function tests in patients with T2DM. Further studies are required to investigate the effect of FS on irisin levels. Trial registration number http://www.irct.ir, code: IRCT20190618043924N1.
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Effects of green tea extract supplementation and endurance training on irisin, pro-inflammatory cytokines, and adiponectin concentrations in overweight middle-aged men.
Bagheri, R, Rashidlamir, A, Ashtary-Larky, D, Wong, A, Grubbs, B, Motevalli, MS, Baker, JS, Laher, I, Zouhal, H
European journal of applied physiology. 2020;(4):915-923
Abstract
PURPOSE Green tea extract (GTE) supplementation has been proposed to possess anti-inflammatory properties. This study assessed the effects of GTE on endurance training (ET) induced changes on irisin, pro-inflammatory cytokines, adiponectin and anthropometric indices in overweight middle-aged males. METHODS Participants were randomly assigned to three groups (n = 15): endurance training + placebo (ET + P), endurance training + green tea extract supplementation (ET + GTE), and no endurance training + placebo (P). The ET intervention consisted of an 8-week training program that included circuit training, fast walking or jogging performed three times/week at a moderate intensity (40-59% of the heart rate reserve). Participants received 500 mg/day GTE using a green tea capsule. Serum concentrations of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), irisin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP) were measured prior to and after the 8-week training intervention. RESULTS Both exercise interventions decreased IL-6 and hs-CRP (p < 0.05), and increased adiponectin (p < 0.01) levels; changes in these variables were greater in the ET + GTE group compared to the ET + P and P groups (p < 0.01). Irisin concentrations increased only in the ET + GTE group and were different from the ET + P and P groups (p < 0.01). There were no changes in TNF-α concentrations in any of the groups. Both exercise interventions (ET + GTE and ET + P) decreased bodyweight, body mass index (BMI), body fat percentage (BFP), and visceral fat area (VFA) (p < 0.05), with greater changes in these variables occurring in the ET + GTE group compared to ET + P and P groups (p < 0.01). CONCLUSION The combination of GTE supplementation and ET produces beneficial anti-inflammatory and metabolic effects, which were greater than those produced by ET alone.
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Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain.
Chandler, PG, Buckle, AM
Cells. 2020;(3)
Abstract
As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage therapeutic proteins based on the FN3 domain are beginning to use native fibronectin function as a point of differentiation. The small and simple structure of monomeric monobodies confers increased tissue distribution and reduced half-life, whilst the absence of disulphide bonds improves stability in cytosolic environments. Where multi-specificity is challenging with an antibody format that is prone to mis-pairing between chains, multiple FN3 domains in the fibronectin assembly already interact with a large number of molecules. As such, multiple monobodies engineered for interaction with therapeutic targets are being combined in a similar beads-on-a-string assembly which improves both efficacy and pharmacokinetics. Furthermore, full length fibronectin is able to fold into multiple conformations as part of its natural function and a greater understanding of how mechanical forces allow for the transition between states will lead to advanced applications that truly differentiate the FN3 domain as a therapeutic scaffold.
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Synergism Effects of Ursolic Acid Supplementation on the Levels of Irisin, C-reactive Protein, IL-6, and TNF-α During High-intensity Resistance Training in Low Activity Men.
Asghari, E, Rashidlamir, A, Hosseini, SRA, Moazzami, M, Samarghandian, S, Farkhondeh, T
Cardiovascular & hematological disorders drug targets. 2020;(2):138-144
Abstract
BACKGROUND Ursolic Acid (UA) is a pentacyclic triterpenoid carboxylic acid which is extracted from plants. UA may enhance the effect of Resistance Training (RT) in human. OBJECTIVE Current research was designed to show the effect of High-Intensity Resistance Training (HIRT) in the presence or absence of UA on the serum levels of irisin, CRP, IL-6 and TNF-α in the low activity men. METHODS The study included twenty-two healthy male HIRT with placebo, supplementation, and HIRT in the presence of UA supplementation. The two groups received eight-week intervention including 2 sets of 8 exercises, with 8~10 repetitions at 70~75% of 1 repetition maximum and a 2 min rest interval between sets, performed 3 times/week. Placebo or UA orally was evaluated as 1 capsule 3 times/day during 8 weeks. The subsequent factors were measured post- and preintervention: C-Reactive Protein (CRP), Irisin, Tumor Necrotic Factor (TNF-α) and Interleukin-6 (IL-6). RESULTS UA supplementation significantly increased the plasma levels of irisin in the HIRT+UA group versus the HIRT+P group (p<0.05). UA treatment also dramatically decreased the plasma levels of CRP, IL-6, and TNF-α in the HIRT+UA group versus the HIRT+P group (p<0.05). CONCLUSION The current data showed that UA-induced an increase in serum irisin and reduction of CRP, IL-6, and TNF-α may have beneficial effects as a chemical for increasing of the effects of HIRT in low activity men.