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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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2.
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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3.
Relationship of Circulating Irisin with Body Composition, Physical Activity, and Cardiovascular and Metabolic Disorders in the Pediatric Population.
Elizondo-Montemayor, L, Mendoza-Lara, G, Gutierrez-DelBosque, G, Peschard-Franco, M, Nieblas, B, Garcia-Rivas, G
International journal of molecular sciences. 2018;(12)
Abstract
Exercise-induced irisin, a recently discovered myokine, has been linked to insulin resistance, obesity, and other diseases in adults; however, information in children is scarce and contradictory. We analyzed the limited evidence of irisin's effects in children and adolescents, and its association with body composition, exercise training, cardiovascular risk factors, and metabolic diseases, as well as the results of dietetic interventions. Both positive and negative correlations between irisin concentrations and body mass index, fat mass, fat-free mass, and other anthropometric parameters were found. Likewise, contradictory evidence was shown associating irisin plasma levels with cardiovascular and metabolic parameters such as glucose, insulin resistance, and cholesterol and other lipid and fatty acid plasma levels in healthy children, as well as in those with obesity and the metabolic syndrome. Gender, puberty, and hormonal differences were also examined. Furthermore, important contradictory findings according to the type and duration of exercise and of dietetic interventions in healthy and unhealthy subjects were demonstrated. In addition, correlations between mother⁻infant relations and circulating irisin were also identified. This review discusses the potential role of irisin in health and disease in the pediatric population.
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4.
Chronic Exercise Training and Circulating Irisin in Adults: A Meta-Analysis.
Qiu, S, Cai, X, Sun, Z, Schumann, U, Zügel, M, Steinacker, JM
Sports medicine (Auckland, N.Z.). 2015;(11):1577-88
Abstract
BACKGROUND Irisin is a newly discovered hormone that is proposed to be a promising therapeutic target in obesity and type 2 diabetes. It has received remarkable attention recently, while inconsistent results have been shown regarding its association with chronic exercise training in adults. OBJECTIVE The aim of this study was to evaluate the effects of chronic exercise training on circulating (plasma/serum) irisin in adults by meta-analyzing randomized controlled trials (RCTs) and non-randomized studies (NRSs) separately. METHODS We conducted a search of the PubMed, Web of Science and Cochrane Library databases from January 2012 to September 2014 for studies published in English. Studies were included if they had an assessment of chronic (≥8 weeks) exercise training effects on circulating irisin in the general or clinical population (mean age ≥18 years) with reported outcomes of circulating irisin, and involved more than five participants. Pooled effect sizes (Cohen's d) with 95 % confidence intervals (CIs) for changes in circulating irisin were calculated by a random-effects model. Subgroup analyses were performed to evaluate the association between exercise modes and changes in circulating irisin. RESULTS Of the 181 articles screened, 12 studies in eight articles were included, of which three were RCTs and nine were NRSs. In the three RCTs (a total of 173 healthy, untrained participants), chronic exercise training was associated with a moderate and significant overall effect in decreasing circulating irisin compared with the control (d = -0.46; 95 % CI -0.76 to -0.15). Chronic resistance exercise training showed a moderate and significant effect in decreasing circulating irisin compared with the control (d = -0.41; 95 % CI -0.75 to -0.06), while endurance exercise training only had a trend (d = -0.64; 95 % CI -1.32 to 0.04). In the nine NRSs (a total of 113 intervention participants), chronic exercise training was associated with a trivial and non-significant overall effect in decreasing circulating irisin compared with baseline (d = -0.04; 95 % CI -0.30 to 0.23). CONCLUSIONS Chronic exercise training leads to significantly decreased circulating irisin levels in the RCTs, while evidence remains inconclusive in the NRSs. Well-designed RCTs that measure dietary intake and report changes of body fat percentage or insulin sensitivity/resistance index following chronic exercise training are required to confirm these findings.
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5.
Three new players in energy regulation: preptin, adropin and irisin.
Aydin, S
Peptides. 2014;:94-110
Abstract
Homeostasis of energy is regulated by genetic factors, food intake, and energy expenditure. When energy input is greater than expenditure, the balance is positive, which can lead to weight gain and obesity. When the balance is negative, weight is lost. Regulation of this homeostasis is multi-factorial, involving many orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) peptide hormones. Peripheral tissues are now known to be involved in weight regulation and research on its endocrine characteristics proceeds apace. Preptin with 34 amino acids (MW 3948 Da), adropin with 43 amino acids and a molecular weight of (4999 Da), and irisin with 112 amino acids (12587 Da), are three newly discovered peptides critical for regulating energy metabolism. Preptin is synthesized primarily in pancreatic beta cells, and adropin mainly in the liver and brain, and many peripheral tissues. Irisin, however, is synthesized principally in the heart muscle, along with peripheral tissues, including salivary glands, kidney and liver. The prime functions of preptin and adropin include regulating carbohydrate, lipid and protein metabolisms by moderating glucose-mediated insulin release. Irisin is an anti-obesitic and anti-diabetic hormone regulating adipose tissue metabolism and glucose homeostasis by converting white to brown adipose tissue. This review offers a historical account of these discovery and function of these peptides, including their structure, and physiological and biochemical properties. Their roles in energy regulation will be discussed. Their measurement in biological fluids will be considered, which will lead to further discussion of their possible clinical value.
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6.
Fibronectin type II (FnII)-like modules regulate gelatinase A activity.
Hornebeck, W, Bellon, G, Emonard, H
Pathologie-biologie. 2005;(7):405-10
Abstract
Gelatinase A, a member of the matrix metalloproteinase family, contains three fibronectin type II (FnII)-like modules that are inserted within its catalytic domain. These FnII modules, defined as exosites, play an essential role in targeting the enzyme to matrix macromolecules, a process which can down-regulate membrane-type metalloproteinase-driven progelatinase A activation. The exosite/substrate-directed gelatinase inhibitors has been proposed as an alternative approach to disappointing active site-directed inhibitors, to control gelatinase A activity. In preliminary experiments, we evidenced that long-chain unsaturated fatty acids could bind preferentially to the first FnII module of gelatinase A. This interaction inhibits the activity of this enzyme towards proteins (type I gelatin and collagen) and an octapeptide substrate, with K(i) in the micromolar range. Since gelatinase A-catalyzed matrix proteolysis might display a positive or negative influence (depending on the substrate cleaved), the design of exosite-specific compounds for noncatalytic targeting of gelatinase A would necessitate an extensive degradomic analysis.
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7.
Sensing the host environment: recognition of hemoglobin by the pathogenic yeast Candida albicans.
Pendrak, ML, Yan, SS, Roberts, DD
Archives of biochemistry and biophysics. 2004;(2):148-56
Abstract
Adhesion to host cells and tissues is important for several steps in the pathogenesis of disseminated Candida albicans infections. Although such adhesion is evident in vivo and for C. albicans grown in vitro in complex medium, some adhesive activities are absent when cultures are grown in defined media. However, addition of hemoglobin to defined media restores binding and adhesion to several host proteins. This activity of hemoglobin is independent of iron acquisition and is mediated by a cell surface hemoglobin receptor. In addition to regulating expression of adhesion receptors, hemoglobin rapidly induces expression of several genes. One of these, a heme oxygenase, allows the pathogen to utilize exogenous heme or hemoglobin to acquire iron and to produce the cytoprotective molecules alpha-biliverdin and carbon monoxide. The specific recognition of and responses to hemoglobin demonstrate a unique adaptation of C. albicans to be both a commensal and an opportunistic pathogen in humans.