Antioxidant Effects of Irisin in Liver Diseases: Mechanistic Insights

Oxidative stress is a crucial factor in the development of various liver diseases. Irisin, a metabolic hormone discovered in 2012, is mainly produced by proteolytic cleavage of fibronectin type III domain containing 5 (FNDC5) in skeletal muscles. Irisin is induced by physical exercise, and a rapidly growing body of literature suggests that irisin is, at least partially, responsible for the beneficial effects of regular exercise. The major biological function of irisin is believed to be involved in the maintenance of metabolic homeostasis. However, recent studies have suggested the therapeutic potential of irisin against a variety of liver diseases involving its antioxidative function. In this review, we aim to summarize the accumulating evidence demonstrating the antioxidative effects of irisin in liver diseases, with an emphasis on the current understanding of the potential molecular mechanisms.

The Role of Physical Exercise Intesity to Irisin Levels on Overweight and Obese

Highlight:The differences in intensity physical exercise mechanisms associated with increased irisin secretion in overweight and obese subjects were determined.The secretion of irisin in the right intensity blood on obesity can be reduced because the calories were balanced. Abstract:Physical exercise is a non-pharmacological therapy that can secrete various types of myokines to treat obesity problems. One of the myokines that play a role is irisin. Irisin is a polypeptide hormone with 112 amino acid residues that are synthesized in skeletal muscle after the proteolytic precursor cleavage of fibronectin type III domain-containing protein 5 (FNDC5). The release of irisin in the blood circulation will stimulate the browning process in white fat tissue by inducing the expression of uncoupling protein-1 (UCP-1) through signaling p38 mitogen-activated protein kinase (p38-MAPK) to increase energy expenditure, thermogenesis and reduce fat accumulation. This study described the differences in intensity of physical exercise mechanisms associated with the increased irisin secretion in overweight and obese subjects. This study was designed as a literature review that involved studies from research journals in the last 10 years concerning humans from some databases, such as Science Direct, PubMed, and Google Scholar. This study also discussed the relationship between the intensity of physical exercise and the synthesis, secretion, circulation, and regulation of irisin in preventing obesity.

Comparative Genomic Characterization of Buffalo Fibronectin Type III Domain Proteins: Exploring the Novel Role of FNDC5/Irisin as a Ligand of Gonadal Receptors

FN-III proteins are widely distributed in mammals and are usually involved in cellular growth, differentiation, and adhesion. The FNDC5/irisin regulates energy metabolism and is present in different tissues (liver, brain, etc.). The present study aimed to investigate the physiochemical characteristics and the evolution of FN-III proteins and FNDC5/irisin as a ligand targeting the gonadal receptors including androgen (AR), DDB1 and CUL4 associated factor 6 (DCAF6), estrogen-related receptor β (ERR-β), estrogen-related receptor γ (ERR-γ), Krüppel-like factor 15 (KLF15), and nuclear receptor subfamily 3 group C member 1 (NR3C1). Moreover, the putative role of irisin in folliculogenesis and spermatogenesis was also elucidated. We presented the molecular structure and function of 29 FN-III genes widely distributed in the buffalo genome. Phylogenetic analysis, motif, and conserved domain pattern demonstrated the evolutionary well-conserved nature of FN-III proteins with a variety of stable to unstable, hydrophobic to hydrophilic, and thermostable to thermo-unstable properties. The comparative structural configuration of FNDC5 revealed amino acid variations but still the FNDC5 structure of humans, buffalo, and cattle was quite similar to each other. For the first time, we predicted the binding scores and interface residues of FNDC5/irisin as a ligand for six representative receptors having a functional role in energy homeostasis, and a significant involvement in folliculogenesis and spermatogenesis in buffalo.

GLP-1 Induces the Expression of FNDC5 Derivatives That Execute Lipolytic Actions

Multiple GLP-1-derived therapeutics are clinically used to treat type 2 diabetes and obesity. However, the underlying mechanism of how these drugs regulate the body weight of obese patients remains incompletely understood. Here, we report that the lipolysis effects of GLP-1 on β cells can depend on its induced expression of fibronectin type III domain containing 5 (FNDC5). The transmembrane FNDC5 is a precursor of the recently identified hormone irisin that possesses a range of bioactivities, including anti-obesity and anti-diabetes. We revealed that GLP-1 upregulates the expression and secretion of FNDC5 in β cells, while GLP-1 itself fails to activate the lipolysis genes in FNDC5-knockout β cells. In addition, liraglutide, a clinically used GLP-1 receptor agonist, induced the expression of FNDC5 in mouse pancreas and brain tissues and increased the serum level of secreted FNDC5. Furthermore, we observed the expression of the well-known membrane-associated FNDC5 and a novel, secretable FNDC5 (sFNDC5) isoform in β cells and multiple rat tissues. Recombinant sFNDC5 stimulated lipolysis of wild type and FNDC5-knockout β cells. This new isoform further induced lipolysis and browning of adipocytes, and similar to irisin, executed potent anti-obesity activities in an obese mouse model. Overall, our studies provided new mechanistic insights into GLP-1’s anti-obesity actions in which GLP-1 induces the secretion of FNDC5 derivatives from its responsive organs that then mediate its anti-obesity activities.

Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody

Angiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application. Here, we develop a human Tie2-agonistic antibody (hTAAB), which targets the membrane proximal fibronectin type III domain of Tie2 distinct from the Angpt-binding site. Our Tie2/hTAAB complex structures reveal that hTAAB tethers the preformed Tie2 homodimers into polygonal assemblies through specific binding to Tie2 Fn3 domain. Notably, the polygonal Tie2 clustering induced by hTAAB is critical for Tie2 activation and are resistant to antagonism by Angpt2. Our results provide insight into the molecular mechanism of Tie2 clustering and activation mediated by hTAAB, and the structure-based humanization of hTAAB creates a potential clinical application.

Irisin: A Promising Target for Ischemia-Reperfusion Injury Therapy

Ischemia-reperfusion injury (IRI) is defined as the total combined damage that occurs during a period of ischemia and following the recovery of blood flow. Oxidative stress, mitochondrial dysfunction, and an inflammatory response are factors contributing to IRI-related damage that can each result in cell death. Irisin is a polypeptide that is proteolytically cleaved from the extracellular domain of fibronectin type III domain-containing protein 5 (FNDC5). Irisin acts as a myokine that potentially mediates beneficial effects of exercise by reducing oxidative stress, improving mitochondrial fitness, and suppressing inflammation. The existing literature also suggests a possible link between irisin and IRI, involving mechanisms similar to those associated with exercise. This article will review the pathogenesis of IRI and the potential benefits and current limitations of irisin as a therapeutic strategy for IRI, while highlighting the mechanistic correlations between irisin and IRI.

The Emerging Role of Irisin in Cardiovascular Diseases

Irisin, a novel hormone like polypeptide, is cleaved and secreted by an unknown protease from a membrane‐spanning protein, FNDC5 (fibronectin type III domain‐containing protein 5). The current knowledge on the biological functions of irisin includes browning white adipose tissue, regulating insulin use, and anti‐inflammatory and antioxidative properties. Dysfunction of irisin has shown to be involved in cardiovascular diseases such as hypertension, coronary artery disease, myocardial infarction, and myocardial ischemia–reperfusion injury. Moreover, irisin gene variants are also associated with cardiovascular diseases. In this review, we discuss the current knowledge on irisin‐mediated regulatory mechanisms and their roles in the pathogenesis of cardiovascular diseases.

Irisin, Energy Homeostasis and Male Reproduction

Irisin is a novel skeletal muscle- and adipose tissue-secreted peptide. It is conventionally regarded as an adipomyokine and is a cleaved fragment of Fibronectin type III domain-containing protein 5 (FNDC5). It is involved in the browning of white adipose tissue, glucose tolerance, and reversing of metabolic disruptions. Fertility is closely linked to energy metabolism and the endocrine function of the adipose tissue. Moreover, there is established association between obesity and male infertility. Irisin bears strong therapeutic promise in obesity and its associated disorders, as well as shown to improve male reproductive functions. Thus, irisin is a molecule of great interest in exploring the amelioration of metabolic syndrome or obesity-induced male infertility. In this review we aim to enumerate the most significant aspects of irisin actions and discuss its involvement in energy homeostasis and male reproduction. Though current and future research on irisin is very promiscuous, a number of clarifications are still needed to reveal its full potential as a significant medicinal target in several human diseases including male infertility.

Differential expression of fibronectin type III domain containing 5 in human epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer (1). We performed discovery of genes associated with epithelial ovarian cancer and of the high-grade serous ovarian cancer (HGSC) subtype, using published and public microarray data (2, 3) to compare global gene expression profiles of normal ovary or fallopian tube with that of primary tumors from women diagnosed with epithelial ovarian cancer or HGSC. We identified the gene encoding fibronectin type III domain containing 5, FNDC5, as among the genes whose expression was most different in epithelial ovarian cancer as compared to the normal fallopian tube. FNDC5 expression was significantly lower in high-grade serous ovarian tumors relative to normal fallopian tube. These data indicate that expression of FNDC5 is perturbed in epithelial ovarian cancers broadly and in ovarian cancers of the HGSC subtype. FNDC5 may be relevant to pathways underlying ovarian cancer initiation (transformation) or progression.

LncRNA ELFN1-AS1 Upregulates TRIM29 to Promote Gastric Cancer Progression by Suppressing miR-211-3p

BackgroundExtracellular leucine rich repeat and fibronectin type III domain containing 1-antisense RNA 1 (ELFN1-AS1) was upregulated in tumors. Nevertheless, the biological functions of ELFN1-AS1 in gastric cancer are not fully understood.MethodsThe ELFN1-AS1, miR-211-3p and TRIM29 expression levels were determined by reverse transcription-quantitative PCR. CCK8, EDU and colony formation assays were done to test the GC cell vitality. The migratory and invasive capabilities of GC cells were further measured by transwell invasion and cell scratch assays. The ceRNA activity of ELFN1-AS1 for TRIM29 via miR-211-3pp was ascertained through pull down, RIP and luciferase reporter assays.ResultsELFN1-AS1 and TRIM29 were robustly expressed in gastric cancer tissues and negatively associated overall survival time of patients. The ELFN1-AS1 silence blocked the proliferation, migration and invasion of GC cells. The oncogenic role of ELFN1-AS1 was recognized to be modulated by miR-211-3pp, which competitively bind to 3'UTR TRIM29 and resulted in the reduced expression of TRIM29.ConclusionELFN1-AS1 maintained the tumorigensis of GC cells by ELFN1-AS1/miR-211-3pp/TRIM29 axis, suggesting that intervention targeting this axis may be warranted for GC treatment.