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    Corrigendum to "Irisin alleviates liver ischemia-reperfusion injury by inhibiting excessive mitochondrial fission, promoting mitochondrial biogenesis and decreasing oxidative stress" [Redox Biol. 20 (2019) 296-306]. Bi Jianbin,Zhang Jia,Ren Yifan,Du Zhaoqing,Li Qingshan,Wang Yue,Wei Shasha,Yang Lifei,Zhang Jingyao,Liu Chang,Lv Yi,Wu Rongqian Redox biology 10.1016/j.redox.2019.101193
    Down-Regulation of Soluble α-Klotho is Associated with Reduction in Serum Irisin Levels in Chronic Obstructive Pulmonary Disease. Kureya Yuko,Kanazawa Hiroshi,Ijiri Naoki,Tochino Yoshihiro,Watanabe Tetsuya,Asai Kazuhisa,Hirata Kazuto Lung PURPOSE:The klotho gene was originally identified as a putative aging-suppressor gene. Klotho-depleted mice display a shortened life span and exhibit a variety of premature aging-related phenotypes such as pulmonary emphysema and sarcopenia. This study was designed to determine the roles of secreted-type klotho protein on lung and skeletal muscle in chronic obstructive pulmonary disease (COPD). METHODS:Serum α-klotho and irisin levels were assayed in 16 non-smokers, 13 smokers without COPD, and 24 smokers with COPD. Moreover, we examined correlations between soluble α-klotho levels and the results of lung function test, cardiopulmonary exercise test (CPET), and skeletal muscle function in smokers with COPD. RESULTS:Soluble α-klotho levels were significantly lower in smokers with COPD compared to non-smokers and smokers without COPD. In smokers with COPD, those levels did not significantly correlate with any parameters of lung function test. In CPET, peak VO2 significantly correlated with FEV1 (% predicted) (r = 0.76, p = 0.0003) and DLCO (% predicted) (r = 0.62, p = 0.003). In contrast, soluble α-klotho levels did not significantly correlate with peak VO2. Irisin levels were also significantly lower in smokers with COPD. Moreover, there was a significant correlation between soluble α-klotho and serum irisin levels (r = 0.61, p = 0.004). CONCLUSIONS:Our findings could provide a critical first step to understanding the impacts of soluble α-klotho on skeletal muscle in COPD and may lead to the identification of new molecular targets for the treatment of COPD. 10.1007/s00408-016-9870-7
    Neurodegenerative disease treatments by direct TNF reduction, SB623 cells, maraviroc and irisin and MCC950, from an inflammatory perspective - a Commentary. Clark I A,Vissel B Expert review of neurotherapeutics : The importance of excessive cerebral tumor necrosis factor (TNF) concentrations as one of the central tenets of the pathogenesis of the neurodegenerative diseases is now widely known, but variably accepted. : Here we update the field by including material that is freely available on the large databases, particularly PubMed. We include the therapeutic outcomes with etanercept (a widely used specific anti-TNF biological), XPro1595 (a new double negative TNF inhibitor), 3,6-dithiothalidomide, implanted SB623 stem cells, maraviroc (a CCR5 inhibitor used to treat AIDS), MCC950 (an NLRP3 inhibitor), and changes in the hormone irisin. : Remarkably, considering the ample literature that links SB623 cells, maraviroc, MCC950 and irisin to TNF, these publications do not mention this cytokine, and therefore not their implicit involvement with controlling its cerebral levels. With regard to developments demonstrated by MCC950, we note that DAMPs and PAMPs recognize and activate both TLRs and inflammasomes in these disease states. Here, as in other illnesses, data suggests that preventing a pathogenic interaction could be achieved through shutting down either of these arms of innate immunity. 10.1080/14737175.2019.1618710
    Blind Spot for Sedentarism: Redefining the Diseasome of Physical Inactivity in View of Circadian System and the Irisin/BDNF Axis. Zsuga Judit,More Csaba E,Erdei Tamas,Papp Csaba,Harsanyi Szilvia,Gesztelyi Rudolf Frontiers in neurology The term "diseasome of physical inactivity" was coined by Pedersen to explain clustering of chronic diseases linked to physical inactivity. Accordingly, physical inactivity contributes to the accumulation of visceral fat, which, generates chronic low-grade systemic inflammation, contributes to emergence of chronic, non-communicable diseases. Diversity of these disorders posits the possible involvement of a supraphysiological system. Hypothesis driven literature search and deductive reasoning was used to review relevant literature and formulate a novel theory. We have identified the circadian system, omnipresent in virtually every cell, as a possible vehicle for brain muscle crosstalk, explaining some aspects of the diseasome of physical inactivity This system is hierarchically organized, with the suprachiasmatic nucleus (SCN) being the master clock that entrains to the dark/light cycle and synchronizes subsidiary molecular clocks in the periphery. Insufficient photic entrainment also causes chronic disease evolution. The recently identified irisin, was shown to induce brain-derived neurotrophic factor (BDNF) production in several brain areas. BDNF assumes significant role in gating light's influence in the retinohypothalamic synapse, by having a permissive effect on glutamate signal transduction underlying photic entrainment. Here we provide theoretical evidence to support the hypothesis that irisin may facilitate photic entrainment of the SCN, BDNF. By this irisin opens up possible pathways for peripheral non-photic entrainment signals to exert influence on the master clock that is otherwise resistant to these. Furthermore, we suggest that intertwining processes of circadian, redox, inflammatory, and myokine systems lay underneath the diseasome of physical inactivity. 10.3389/fneur.2018.00818
    Can irisin be a linker between physical activity and brain function? Zhang Jing,Zhang Weizhen Biomolecular concepts Irisin was initially discovered as a novel hormone-like myokine released from skeletal muscle during exercise to improve obesity and glucose dysfunction by stimulating the browning of white adipose tissue. Emerging evidence have indicated that irisin also affects brain function. FNDC5 mRNA and FNDC5/irisin immunoreactivity are present in various regions of the brain. Central irisin is involved in the regulation of neural differentiation and proliferation, neurobehavior, energy expenditure and cardiac function. Elevation of peripheral irisin level stimulates hippocampal genes related to neuroprotection, learning and memory. In this brief review, we summarize the current understanding on neuronal functions of irisin. In addition, we discuss the pros and cons for this molecule as a potential messenger mediating the crosstalk between skeletal muscle and central nervous system during exercise. 10.1515/bmc-2016-0012
    The immunomodulatory role of irisin on osteogenesis via AMPK-mediated macrophage polarization. Ye Wenbin,Wang Jiangze,Lin Dasheng,Ding Zhenqi International journal of biological macromolecules Bone healing is thought to be closely related to macrophages. Irisin, a cleaved hormone-like myokine, is well known to participate in immunoregulation and regulates bone metabolism. However, whether irisin could influence osteogenesis by affecting macrophage polarization is remain unknown. Here, the present study aims to investigate the potential immunomodulatory role of irisin on macrophages polarization and its subsequent impact on osteogenesis. We demonstrated that irisin increased cell viability without toxic effect in both Raw264.7 macrophages and MC3T3-E1 cells. Furthermore, irisin treatment polarized M0 and M1 macrophages towards M2 phenotype, with increased expression of CD206-APC, ARG-1 and TGF-β1, and decreased expression of CD86-PE and TNF-α. In addition, the direct co-cultured test of Raw264.7 macrophages and pre-osteoblastic MC3T3-E1 cells showed that irisin-treated M0 and M1 macrophages promoted osteogenesis with obvious formation of mineralized particles. Interestingly, irisin exposure robustly activated AMPK-α signaling, as manifested by increased expression of phosphorylated AMPK-α. Knockdown of AMPK-α by siRNA significantly suppressed the phosphorylation of AMPK-α, abrogated irisin-induced polarization of M2 phenotype, and inhibited the osteogenic ability of Raw264.7 macrophages. Taken together, our findings showed that irisin-induced M2 polarization enhanced osteogenesis in osteoblasts, and this effect might be associated with activation of AMPK. 10.1016/j.ijbiomac.2019.12.028
    Anti-Inflammatory Properties of Irisin, Mediator of Physical Activity, Are Connected with TLR4/MyD88 Signaling Pathway Activation. Mazur-Bialy Agnieszka Irena,Pocheć Ewa,Zarawski Marcin International journal of molecular sciences Irisin, an adipomiokine known as a mediator of physical activity, induces the browning of adipose tissue and it has potentially protective properties in the development of obesity-related states, such as insulin resistance, arteriosclerosis, and type 2 diabetes. Despite numerous studies conducted on this factor, still little is known about its impact on the functioning of immunocompetent cells, but its potential anti-inflammatory properties were previously suggested. In the current study we investigated the role of irisin (0-100 nM) in the downstream pathway activation of Toll-like receptor 4 (TLR4) in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS; 100 ng/mL). The results have shown that irisin in high concentrations (50, 100 nM) significantly decreased the TLR4 and MyD88 protein levels, as well as the phosphorylation of nuclear factor-κB (NF-κB), consequently leading to the reduction in the release of crucial pro-inflammatory cytokines. The above was confirmed for interleukin 1β (IL-1β), tumor necrosis factor α (TNFα), interleukin 6 (IL-6), keratinocyte chemoattractant (KC), monocyte chemotactic protein 1 (MCP-1), as well as for high mobility group box 1 (HMGB1). Moreover, our results indicate that this effect is connected with irisin's impact on the phosphorylation of mitogen-activated protein kinases (MAPKs), where a significant reduction in p-JNK and p-ERK but not p-p38 was observed. In conclusion, these data suggest that irisin has potentially anti-inflammatory properties connected with the downregulation of downstream pathways of TLR4/MyD88. 10.3390/ijms18040701
    Beneficial Effect of Voluntary Exercise on Experimental Colitis in Mice Fed a High-Fat Diet: The Role of Irisin, Adiponectin and Proinflammatory Biomarkers. Mazur-Bialy Agnieszka Irena,Bilski Jan,Wojcik Dagmara,Brzozowski Bartosz,Surmiak Marcin,Hubalewska-Mazgaj Magdalena,Chmura Anna,Magierowski Marcin,Magierowska Katarzyna,Mach Tomasz,Brzozowski Tomasz Nutrients Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms: Crohn's disease and ulcerative colitis. Although the aetiology of IBD is unknown, several factors coming from the adipose tissue and skeletal muscles, such as cytokines, adipokines and myokines, were suggested in the pathogenesis of ulcerative colitis; however, it has not been extensively studied whether voluntary exercise can ameliorate that disorder. We explored the effect of moderate exercise (i.e., voluntary wheel running) on the disease activity index (DAI), colonic blood flow (CBF), plasma irisin and adiponectin levels and real-time PCR expression of proinflammatory markers in mesenteric fat in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis fed a high-fat diet (HFD) compared to those on a standard chow diet (SD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant fall in CBF, some increase in colonic tissue weight and a significant increase in the plasma levels of tumour necrosis factor-alpha (TNF-α), IL-6, monocyte chemotactic protein 1 (MCP-1) and IL-13 ( < 0.05). In sedentary HFD mice, colonic lesions were aggravated, colonic tissue weight increased and the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels significantly increased. Simultaneously, a significant decrease in the plasma irisin and adiponectin levels was observed in comparison with SD mice ( < 0.05). Exercise significantly decreased macroscopic and microscopic colitis, substantially increased CBF and attenuated the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels while raising the plasma irisin and the plasma and WAT concentrations of adiponectin in HFD mice ( < 0.05). We conclude that: (1) experimental colitis is exacerbated in HFD mice, possibly due to a fall in colonic microcirculation and an increase in the plasma and mesenteric fat content of proinflammatory biomarkers; and (2) voluntary physical activity can attenuate the severity of colonic damage in mice fed a HFD through the release of protective irisin and restoration of plasma adiponectin. 10.3390/nu9040410
    Superiority of the Non-Glycosylated Form Over the Glycosylated Form of Irisin in the Attenuation of Adipocytic Meta-Inflammation: A Potential Factor in the Fight Against Insulin Resistance. Mazur-Bialy Agnieszka Irena Biomolecules Irisin is an adipomyokine that promotes the browning of white adipose tissue and exhibits protective potential against the development of insulin resistance and type 2 diabetes. In our bodies, it occurs in its glycosylated form (G-IR): its activity is still poorly understood, because the majority of studies have used its non-glycosylated counterpart (nG-IR). Glycosylation can affect protein function: therefore, the present study attempted to compare the actions of both forms of irisin toward inflammatory activation of the main component of adipose tissue. The study was carried out in a coculture of 3T3 adipocytes and RAW 264.7 macrophages maintained in the presence of nG-IR or G-IR. The impact on vitality and the expression and release of key inflammatory mediators important for insulin resistance and diabetes development were assessed. The studies showed that both forms effectively inhibited the expression and release of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, macrophage chemotactic protein (MCP)-1, high-mobility group box (HMGB1), leptin, and adiponectin. However, in the case of TNF-α, IL-1β, MCP-1, and HMGB1, the inhibition exerted by nG-IR was more prominent than that by G-IR. In addition, only nG-IR significantly inhibited macrophage migration. Here, nG-IR seemed to be the stronger inhibitor of the development of obesity-related inflammation; however, G-IR also had anti-inflammatory potential. 10.3390/biom9090394
    Role of serum levels of irisin and oxidative stress markers in pregnant women with and without gestational diabetes. Usluoğullari Betül,Usluogullari Celil Alper,Balkan Fevzi,Orkmez Mustafa Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology Irisin regulates glucose levels, lipid levels, insulin sensitivity, and low-grade inflammation. Gestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy, and is associated with increased rates of perinatal problems. Oxidative stress biomarkers have a role in the pathogenesis of patients with GDM. In total, 94 patients were included in our study including 46 control patients and 48 patients with GDM. Fasting blood glucose, HOMA-IR, total oxidative stress (TOS), irisin, and oxidative stress index (OSI) levels of the patients were measured. Serum OGTT, OSI, irisin HOMA, TOS, and insulin levels were statistically significantly higher in the patient group than in the control group. This was the first study to investigate the relation between serum irisin levels and oxidative stress markers in patients with GDM. The results revealed that irisin is an oxidative stress marker and a metabolic protective hormone. 10.1080/09513590.2017.1284789
    Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues. Dong Jiangling,Dong Yanjun,Dong Yanlan,Chen Fang,Mitch William E,Zhang Liping International journal of obesity (2005) BACKGROUND/OBJECTIVE:In mice, a high-fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities. SUBJECTS/METHODS:C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using small hairpin RNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their responses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or irisin. Isolated peritoneal macrophages were treated with myostatin or irisin to determine whether myostatin or irisin induce inflammatory mechanisms. RESULTS:In HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In HFD-fed mice, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both the muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue, whereas stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by irisin. Myostatin inhibition increased peroxisome proliferator-activated receptor gamma, coactivator 1α expression and irisin production in the muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types. CONCLUSIONS:These results uncover a metabolic pathway from an increase in myostatin that suppresses irisin leading to the activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well as the shortage of brown/beige fat in obesity. 10.1038/ijo.2015.200
    Irisin, a newly discovered myokine, is a novel biomarker associated with physical activity in patients with chronic obstructive pulmonary disease. Ijiri Naoki,Kanazawa Hiroshi,Asai Kazuhisa,Watanabe Tetsuya,Hirata Kazuto Respirology (Carlton, Vic.) BACKGROUND AND OBJECTIVE:Irisin is a recently identified hormone secreted by skeletal myocytes, which has been proposed to mediate the beneficial effects of exercise. Physical activity has been emphasized as one of the principal targets of the treatment for chronic obstructive pulmonary disease (COPD). This study was designed to evaluate the possibility of using serum irisin level as a novel biomarker associated with physical activity in patients with COPD. METHODS:We measured the serum irisin level in 72 COPD patients and 27 control subjects, and investigated its correlation to pulmonary function parameters, exercise capacity and physical activity level. In addition, we analysed the effects of acute and chronic exercise on serum irisin level. RESULTS:Fat-free mass index was not significantly different between the two study groups. However, lower serum irisin level was observed in COPD patients than in the control subjects (COPD patients: median (interquartile range) 31.6 (22.7-40.4) ng/mL; control subjects: 50.7 (39.3-65.8) ng/mL; P < 0.001). The serum irisin level did not significantly correlate with any pulmonary function parameters and 6-min walk distance. However, serum irisin level was associated with the physical activity level in all subjects. In COPD patients, acute exercise did not affect serum irisin level, but an 8-week exercise training was linked to the significant increase in its level. CONCLUSIONS:Circulating irisin could be used to evaluate physical activity in COPD patients and increased after an 8-week exercise training. Serum irisin level may prove to be a valuable biomarker in clinical follow up of COPD. 10.1111/resp.12513
    Inflammation-induced lymphatic architecture and bone turnover changes are ameliorated by irisin treatment in chronic inflammatory bowel disease. Narayanan S Anand,Metzger Corinne E,Bloomfield Susan A,Zawieja David C FASEB journal : official publication of the Federation of American Societies for Experimental Biology Inflammatory bowel disease (IBD) is a chronic disease with gastrointestinal dysfunction as well as comorbidities such as inflammation-induced bone loss and impaired immune response. Current treatments for IBD all have negative, potentially severe side effects. We aimed to test whether exogenous treatment with irisin, a novel immunomodulatory adipomyokine, could ameliorate IBD-induced lymphatic and bone alterations. Irisin treatment improved both gut and bone outcomes by mitigating inflammation and restoring structure. In the gut, IBD caused colonic lymphatic hyperproliferation into the mucosal and submucosal compartments. This proliferation in the rodent model is akin to what is observed in IBD patient case studies. In bone, IBD increased osteoclast surface and decreased bone formation. Both gut and osteocytes in bone exhibited elevated levels of TNF-α and receptor activator of NF-κB ligand (RANKL) protein expression. Exogenous irisin treatment restored normal colonic lymphatic architecture and increased bone formation rate concurrent with decreased osteoclast surfaces. After irisin treatment, gut and osteocyte TNF-α and RANKL protein expression levels were no different from vehicle controls. Our data indicate that the systemic immunologic changes that occur in IBD are initiated by damage in the gut and likely linked through the lymphatic system. Additionally, irisin is a potential novel intervention mitigating both local inflammatory changes in the gut and distant changes in bone.-Narayanan, S. A., Metzger, C. E., Bloomfield, S. A., Zawieja, D. C. Inflammation-induced lymphatic architecture and bone turnover changes are ameliorated by irisin treatment in chronic inflammatory bowel disease. 10.1096/fj.201800178R
    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 Ehsan,Rashidlamir Amir,Hosseini Seyyed R A,Moazzami Mahtab,Samarghandian Saeed,Farkhondeh Tahereh Cardiovascular & hematological disorders drug targets 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. 10.2174/1871529X19666190918144727
    Relationship between Irisin Concentration and Serum Cytokines in Mother and Newborn. Hernandez-Trejo Maria,Garcia-Rivas Gerardo,Torres-Quintanilla Alejandro,Laresgoiti-Servitje Estibalitz PloS one INTRODUCTION:Irisin is considered to be a myokine and adipokine that may also participate in reproductive functions, as it increases significantly throughout pregnancy. However, the regulation of circulating irisin and its relationship with other cytokines has not been assessed thus far in pregnant women and their offspring. OBJECTIVE:The aim of this study was to evaluate differences in irisin and cytokine concentrations between women at the end of pregnancy and their offspring, as well as the relationship between maternal and newborn irisin and maternal and newborn biomarkers. METHODS:Twenty-eight mother/newborn pairs were included in this study. The following biomarkers were evaluated in maternal venous and arterial umbilical cord blood samples: irisin, 27 cytokine panel, total antioxidant capacity (TAC), total plasma protein, and free fatty acid concentration. RESULTS:The newborns had significantly lower irisin concentrations compared to their mothers (p = 0.03), but this difference was present only in babies born from mothers without labor prior to cesarean section delivery (p = 0.01). No significant differences in maternal and newborn irisin concentrations were found between diabetic and non-diabetic mothers or between overweight/obese and normal weight mothers. A significant positive correlation was found between TAC level and irisin concentration in newborns. Maternal and newborn interleukin (IL)-1β, IL-1RA, IL-5, IL-7, and interferon gamma-induced protein (IP)-10 levels were significantly positively correlated with irisin concentrations in both study groups. In addition, maternal IL1β, IL-5, IL-7, and IP-10 levels positively predicted maternal irisin concentrations. Furthermore, arterial cord blood TAC and IL-1β and IL1-RA levels positively predicted newborn irisin concentrations. Multiple regression analyses showed that maternal IL-13 negatively predicted offspring irisin levels (p = 0.03) and that maternal IL-1β positively predicted newborn irisin concentrations (p = 0.046). CONCLUSION:No evidence was found that serum irisin concentrations in mothers at pregnancy termination or those of their newborns correlated with maternal body mass index, the presence of diabetes mellitus, or free fatty acid levels. However, the results of this study indicated that cytokines might predict irisin concentration in mothers and their offspring, although interactions between irisin levels during pregnancy and the newborn have not yet been fully elucidated. 10.1371/journal.pone.0165229
    Association of Circulating Irisin with Insulin Resistance and Oxidative Stress in Obese Women. Belviranli M,Okudan N,Çelik F Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme Irisin is a myokine/adipokine with potential role in obesity and diabetes. The purpose of the present study was to assess irisin levels and its association with insulin resistance and oxidative stress markers in premenopausal normal-weight and obese women. Ten obese (mean body mass index, 32.65±3.04 kg m) and 10 normal-weight (23.00±2.23 kg m) premenopausal women were involved in the present study. Anthropometric, and body composition parameters, blood chemistry, oxidative stress markers, and irisin concentrations of different groups were measured. Correlation analyses were performed between irisin and other measured parameters. Plasma irisin levels were lower in the obese group than the normal-weight group (p<0.05). Glucose, homeostasis model assessment index (HOMA-IR), and MDA levels in the obese group were higher than that in the normal-weight group (p<0.05). Plasma irisin was negatively correlated with insulin (r=-0.648, p<0.05), HOMA-IR (r=-0.664, p<0.05) and MDA (r=-0.690, p<0.05). These data suggest that irisin levels are decreased with obesity, and irisin may have an antidiabetic and antioxidant effects. 10.1055/s-0042-116155
    Maternal high-fat diet during pregnancy and lactation provokes depressive-like behavior and influences the irisin/brain-derived neurotrophic factor axis and inflammatory factors in male and female offspring in rats. Gawlinska K,Gawlinski D,Przegalinski E,Filip M Journal of physiology and pharmacology : an official journal of the Polish Physiological Society A balanced maternal diet is necessary for the proper health and development of offspring. Recent clinical and preclinical studies have strongly indicated that maternal exposure to a high-fat diet (HFD) can have an irreversible impact on the structure and function of the offspring's brain and affect the immune system, which may predispose the offspring to brain disorders, including depression. The irisin/brain-derived neurotrophic factor (BDNF) axis is a pathway that influences several neurobehavioral mechanisms involved in the pathogenesis of mental disorders. The aim of the present study was to evaluate the influence of a maternal HFD during pregnancy and lactation on depressive-like behavior, serum irisin concentration and hippocampal levels of irisin, BDNF and inflammatory factors (interleukin-1α, interleukin-6 and tumor necrosis factor-α) in adolescent and adult male and female offspring. The main findings indicate that offspring exposed to a maternal HFD are characterized by an increased immobility time in the forced swimming test at both stages of life. Our results showed that a maternal HFD decreased serum and hippocampal irisin levels in females on postnatal day (PND) 28 and decreased the level of interleukin-1α at postnatal days 28 and 63 in the hippocampus. Interestingly, significant age-dependent changes were observed in irisin, BDNF and interleukin levels. To summarize, our study indicates that a maternal HFD during pregnancy and lactation provokes depressive-like behaviour in the offspring. However, despite the observed changes in the levels of irisin and IL-1α in females, further investigations are required to identify the underlying molecular mechanism associated with depressive-like behavior in the offspring of HFD-fed dams. 10.26402/jpp.2019.3.07
    Myokine irisin-induced protection against oxidative stress in vitro. Involvement of heme oxygenase-1 and antioxidazing enzymes superoxide dismutase-2 and glutathione peroxidase. Mazur-Bialy A I,Kozlowska K,Pochec E,Bilski J,Brzozowski T Journal of physiology and pharmacology : an official journal of the Polish Physiological Society Irisin is a recently discovered myokine reported as protective protein released from exercising skeletal muscles. Although myokines were recently reported to possess the antioxidizing properties, the impact of irisin on the functions of macrophages with respect to its anti-inflammatory potential has not been fully elucidated. Here, we determined the ability of irisin to interact with reactive oxygen species (ROS) in RAW 264.7 murine macrophages. The macrophages were pre-incubated with irisin (0 - 50 nM), some of which had undergone additional co-incubation with bacterial lipopolysaccharide (LPS) (100 ng/ml). Cell viability, the reactive oxygen species scavenging potential as well as the mRNA and protein expression of key oxidative stress factors such as superoxide dismutase 1 (SOD-1), superoxide dismutase 2 (SOD-2), glutathione peroxidase (GSH-Px), catalase 9 (Cat-9), nuclear factor (erythroid-derived 2)-like 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) were evaluated. We found that irisin applied in a concentration of 50 nM significantly attenuated the production of harmful HO and this effect appears to be mediated by a significant increase in the expression of key enzymes involved with antioxidative stress pathways including SOD, GSH-Px and Cat-9 predominantly observed after stimulation of these cells with LPS. We conclude that 1) irisin exhibits a potent antioxidant and anti-inflammatory activities in non-stimulated and LPS-stimulated isolated murine macrophages in vitro, and 2) this protective and antioxidative activity of irisin in vitro might be considered as an important component of protective action of this peptide in vivo, especially under condition of exercise. 10.26402/jpp.2018.1.13
    Circulating irisin levels and muscle FNDC5 mRNA expression are independent of IL-15 levels in mice. Quinn LeBris S,Anderson Barbara G,Conner Jennifer D,Wolden-Hanson Tami Endocrine Interleukin-15 (IL-15) and irisin are exercise-induced myokines that exert favorable effects on energy expenditure and metabolism. IL-15 can induce PGC-1α expression, which in turn induces expression of irisin and its precursor, FNDC5. Therefore, the present study tested the hypothesis that increases in circulating irisin levels and muscle FNDC5 mRNA expression are dependent on IL-15. Circulating irisin levels and gastrocnemius muscle FNDC5 mRNA expression were examined following acute exercise in control and IL-15-deleted (IL-15 KO) mice, following injection of IL-15 into IL-15 KO mice, and in transgenic mice with elevated circulating IL-15 levels (IL-15 Tg mice). Circulating IL-15 levels and muscle PGC-1α and PPARδ mRNA expressions were determined as positive controls. No effect of IL-15 deletion on post-exercise serum irisin levels or muscle FNDC5 mRNA expression was detected. While serum IL-15 levels and muscle PGC-1α expression were elevated post-exercise in control mice, both serum irisin levels and muscle FNDC5 expression decreased shortly after exercise in both control and IL-15 KO mice. A single injection of recombinant IL-15 into IL-15 KO mice that significantly increased muscle PPARδ and PGC-1α mRNA expressions had no effect on circulating irisin release, but modestly induced muscle FNDC5 expression. Additionally, serum irisin and gastrocnemius muscle FNDC5 expression in IL-15 Tg mice were similar to those of control mice. Muscle FNDC5 mRNA expression and irisin release are not IL-15-dependent in mice. 10.1007/s12020-015-0607-9
    New insight into the direct anti-inflammatory activity of a myokine irisin against proinflammatory activation of adipocytes. Implication for exercise in obesity. Mazur-Bialy A I,Bilski J,Pochec E,Brzozowski T Journal of physiology and pharmacology : an official journal of the Polish Physiological Society A biological activity of myokine irisin, has been intensively investigated in the context of a browning process occurring in white adipose tissue, but its role as a modulator of immune response has been little studied. The aim of our study was to determine the impact of irisin (0 - 100 nM) on pro-inflammatory activation of adipocyte 3T3 L1 cell line. Irisin reduced in a concentration-dependent manner the expression and activity of major proinflammatory cytokines, e.g. tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) expression and their secretion into cell medium. Moreover, irisin enhanced adiponectin synthesis reversing the effect of the lipopolysaccharide (LPS)-induced attenuation of this adipokine expression. The opposite effect was observed for leptin whose expression increased by LPS and this effect was suppressed by irisin application. A decreased phosphorylation and activation of nuclear factor kappa B (NFκB) in the presence of irisin suggests that mechanism of action irisin involves the inhibition of an inflammatory transcription factor. Irisin exerts also an inhibitory effect on macrophage migration toward chemoattractants present in adipocyte supernatants. Among the specific molecules secreted by adipocytes was monocyte chemotactic protein 1 (MCP-1) whose expression was suppressed by irisn. In majority of experiments irisin was effective in 100 nM concentration but in some of them the inhibitory effects occurred already in a concentration of 50 nM of this peptide. This study for the first time showed that adipocytes are directly affected by irisin and provides an evidence on anti-inflammatory action of irisin on fat cells.
    DSS-induced colitis produces inflammation-induced bone loss while irisin treatment mitigates the inflammatory state in both gut and bone. Metzger Corinne E,Narayanan S Anand,Elizondo Jon P,Carter Anne Michal,Zawieja David C,Hogan Harry A,Bloomfield Susan A Scientific reports Chronic pediatric inflammatory bowel disease (IBD) leads to lack of bone accrual, bone loss, and increased fractures. Presently there is no cure, and many IBD treatments incur negative side effects. We previously discovered treatment with exogenous irisin resolved inflammatory changes in the colon, gut lymphatics, and bone in a mild IBD rodent model. Here we assess irisin treatment in severe IBD induced via dextran sodium sulfate (DSS). Male Sprague Dawley rats (2-mo-old) were untreated (Con) or given 2% DSS in drinking water. In week two, half of each group (Con + Ir and DSS + Ir) received injections of recombinant irisin (i.p., 2x/wk). After 4 weeks, gut inflammation was associated with declines in bone mineral density and cancellous bone volume. Furthermore, elevated osteocyte TNF-α, interleukin-6, RANKL, OPG, and sclerostin corresponded with higher osteoclast surfaces and lower bone formation rate in DSS animals as well as lower ultimate load. While irisin treatment improved colon inflammation, there were no improvements in bone density or bone mechanical properties; however, irisin elevated bone formation rate, decreased osteoclast surfaces, and reduced osteocyte pro-inflammatory factors. These data highlight the negative impact of chronic gut inflammation on bone as well as the therapeutic potential of irisin as an anti-inflammatory treatment. 10.1038/s41598-019-51550-w
    Serum irisin: A prognostic marker for severe acne vulgaris. Mustafa Amany I,El-Shimi Ola S Journal of cosmetic dermatology BACKGROUND:Acne vulgaris is a common chronic inflammatory skin disease involving pilosebaceous units. Adipokines are secreted by adipose tissue and function as signaling networks communicating it with different organs. They may have role in pathogenesis of acne vulgaris and the associated insulin resistance. Irisin, a hormone like myokine, is one of adipokines with anti-inflammatory, anti-oxidant, and anti-diabetic effects. AIMS:We aimed at evaluation of serum irisin level in patients with acne vulgaris to assess its correlation with disease pathogenesis. PATIENTS AND METHODS:Serum irisin level was measured by an ELISA technique in 60 acne vulgaris patients and 60 apparently healthy controls. Insulin resistance was calculated by Homeostasis Model Assessment of Insulin Resistance index. RESULTS:Serum irisin level was significantly lower in acne vulgaris patients than control group (P < 0.001). It showed a significant negative correlation with insulin resistance among patients (P 0.012). Moreover, it was decreasing significantly with the increase in disease severity (P 0.004). CONCLUSIONS:Our results revealed that lower serum irisin not only to be a biomarker of disease pathogenesis but also to be a potential prognostic predictor for severity in acne vulgaris. 10.1111/jocd.12753
    Irisin Exerts Neuroprotective Effects on Cultured Neurons by Regulating Astrocytes. Wang Kexin,Li Hongyan,Wang Hongxing,Wang Jun-Hui,Song Feng,Sun Yu Mediators of inflammation Neurons suffer detrimental effects from -amyloid toxicity in Alzheimer's disease. The exercise hormone, irisin, is found to induce a neuroprotective gene program and facilitates the beneficial effects on cognitive function. But no effort is made to test its direct protective effects on neurons against the A-induced cell toxicity so far. In the present study, we investigated whether irisin could protect neurons against A- (25-35) induced cell damage and explored the possible underlying mechanisms. Primary cell cultures of astrocytes and neurons were established. Conditioned medium from astrocyte was collected for the treatment and biochemistry assay study. To explore the protein expression changes, Western blot and ELISA assays were used in these cell culture models. Exposure of hippocampal neurons to 10 M A (25-35) caused significant reduction on cell viability, and the toxic effect was not significantly reduced by the coadministration of irisin. However, pretreated astrocyte-conditioned medium with irisin for 12 hours notably protected the neurons from the toxicity of A. Also, we found that irisin could attenuate the release of IL-6 and IL-1 from cultured astrocytes and decrease the expression level of COX-2 and phosphorylation of AKT. Last, we found that irisin could reduce NFB activation in astrocyte exposed to A by preventing the phosphorylation and the loss of IB. Our finding may provide novel evidence for the future application of irisin in the treatment of Alzheimer's disease and the memory dysfunction in diabetes mellitus. 10.1155/2018/9070341
    Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury. Chen Ken,Xu Zaicheng,Liu Yukai,Wang Zhen,Li Yu,Xu Xuefei,Chen Caiyu,Xia Tianyang,Liao Qiao,Yao Yonggang,Zeng Cindy,He Duofen,Yang Yongjian,Tan Tao,Yi Jianxun,Zhou Jingsong,Zhu Hua,Ma Jianjie,Zeng Chunyu Science translational medicine Limb remote ischemic preconditioning (RIPC) is an effective means of protection against ischemia/reperfusion (IR)-induced injury to multiple organs. Many studies are focused on identifying endocrine mechanisms that underlie the cross-talk between muscle and RIPC-mediated organ protection. We report that RIPC releases irisin, a myokine derived from the extracellular portion of fibronectin domain-containing 5 protein (FNDC5) in skeletal muscle, to protect against injury to the lung. Human patients with neonatal respiratory distress syndrome show reduced concentrations of irisin in the serum and increased irisin concentrations in the bronchoalveolar lavage fluid, suggesting transfer of irisin from circulation to the lung under physiologic stress. In mice, application of brief periods of ischemia preconditioning stimulates release of irisin into circulation and transfer of irisin to the lung subjected to IR injury. Irisin, via lipid raft-mediated endocytosis, enters alveolar cells and targets mitochondria. Interaction between irisin and mitochondrial uncoupling protein 2 (UCP2) allows for prevention of IR-induced oxidative stress and preservation of mitochondrial function. Animal model studies show that intravenous administration of exogenous irisin protects against IR-induced injury to the lung via improvement of mitochondrial function, whereas in UCP2-deficient mice or in the presence of a UCP2 inhibitor, the protective effect of irisin is compromised. These results demonstrate that irisin is a myokine that facilitates RIPC-mediated lung protection. Targeting the action of irisin in mitochondria presents a potential therapeutic intervention for pulmonary IR injury. 10.1126/scitranslmed.aao6298
    Decreased levels of irisin, a skeletal muscle cell-derived myokine, are related to emphysema associated with chronic obstructive pulmonary disease. Sugiyama Yukari,Asai Kazuhisa,Yamada Kazuhiro,Kureya Yuko,Ijiri Naoki,Watanabe Tetsuya,Kanazawa Hiroshi,Hirata Kazuto International journal of chronic obstructive pulmonary disease BACKGROUND:Cigarette smoking-induced oxidant-antioxidant imbalance is a factor that contributes to the pathogenesis of COPD through epithelial cell apoptosis. Irisin is a skeletal muscle cell-derived myokine associated with physical activity. Irisin is also known to decrease oxidant-induced apoptosis in patients with diabetes mellitus. However, the correlation between irisin and emphysema in COPD and its role in epithelial cell apoptosis remains unknown. SUBJECTS AND METHODS:Forty patients with COPD were enrolled in this study. Pulmonary function tests and measurements of the percentage of low-attenuation area on high-resolution computed tomography images were performed, and the results were evaluated for correlation with serum irisin levels. The effect of irisin on cigarette-smoke extract-induced A549 cell apoptosis and the expression of Nrf2, a transcription factor for antioxidants, was also examined in vitro. RESULTS:Serum irisin levels were significantly correlated with lung diffusing capacity for carbon monoxide divided by alveolar volume (=0.56, <0.01) and percentage of low-attenuation area (=-0.79, <0.01). Moreover, irisin significantly enhanced Nrf2 expression (<0.05) and reduced cigarette-smoke extract-induced A549 cell apoptosis (<0.05). CONCLUSION:Decreased serum irisin levels are related to emphysema in patients with COPD and involved in epithelial apoptosis, resulting in emphysema. Irisin could be a novel treatment for emphysema in patients with COPD. 10.2147/COPD.S126233
    The diagnostic value of irisin in patients with acute abdominal pain: A preliminary study. Yeniocak Selman,Karcıoğlu Özgür,Kalkan Asım,Saraç Fatma,Akgül Karadana Gökçe,Keklikkıran Zehra Zeynep,Gümüş Alper,Koldaş Macit,Korkut Semih Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery : TJTES BACKGROUND:The aim of this study was to investigate the prognostic value of irisin by examining the serum level of this smooth muscle protein in patients presenting at the emergency department (ED) with acute abdominal pain. METHODS:This research was performed as a single-center, prospective, cross-sectional study. In all, 213 adult patients presenting at the ED with acute abdominal pain and 140 healthy controls were enrolled. The serum irisin level was correlated with the leukocyte, C-reactive protein, amylase, and creatine kinase values. The irisin level was compared between groups of those who were admitted or discharged, and those who received surgical or medical treatment. RESULTS:The mean irisin level of the 213 patients and the 140 controls was 6.81±3.17 mcg/mL vs. 5.69±2.08 mcg/mL. The mean irisin value of the hospitalized patients (7.98±3.11 mcg/mL) was significantly higher than that of the discharged patient group (6.38±3.09 mcg/mL) and the controls (control vs. discharged: p=0.202; control vs. hospitalized: p<0.001; discharged vs. hospitalized: p=0.001). When compared with that of the control group, the irisin level was significantly higher in patients with gall bladder diseases, urolithiasis, and acute appendicitis (p=0.001, p=0.007, p=0.007). CONCLUSION:The serum irisin level in patients with abdominal pain may serve as a guide in diagnostic decision-making and determining the prognosis for cases of acute abdominal pain involving luminal obstruction in tubular intra abdominal organs. 10.5505/tjtes.2018.29235
    Irisin suppresses the migration, proliferation, and invasion of lung cancer cells via inhibition of epithelial-to-mesenchymal transition. Shao Lei,Li Huanjie,Chen Jian,Song Haibo,Zhang Yuzhu,Wu Fei,Wang Wenjuan,Zhang Wen,Wang Fang,Li Hui,Tang Dongqi Biochemical and biophysical research communications Irisin is involved in promoting metabolism, immune regulation, and affects chronic inflammation in many systemic diseases, including gastric cancer. However, the role of irisin in lung cancer is not well characterized. To determine whether irisin has a protective effect against lung cancer, we cultured A549 and NCI-H446 lung cancer cells and treated them with irisin. We detected the proliferation by MTT assay, and assessed the migration and invasion of the cells by scratch wound healing assay and Tran-swell assay. The expression levels of epithelial-to-mesenchymal transition (EMT) markers and the related signaling pathways were detected by western blot analysis. Meanwhile, an inhibitor of PI3K was used to investigate the effect of irsin. Finally, the expression of Snail was detected. We demonstrated that irisin inhibits the proliferation, migration, and invasion of lung cancer cells, and has a novel role in mediating the PI3K/AKT pathway in the cells. Irisin can reverse the activity of EMT and inhibit the expression of Snail via mediating the PI3K/AKT pathway, which is a key regulator of Snail. These results revealed that irisin inhibited EMT and reduced the invasion of lung cancer cells via the PI3K/AKT/Snail pathway. 10.1016/j.bbrc.2016.12.084
    Irisin acts as a regulator of macrophages host defense. Mazur-Bialy Agnieszka Irena Life sciences AIM:Irisin, the adipomyokine, released mainly by exercised muscles, participate in the browning of adipose tissue and contribute to the restriction of insulin resistance and diabetes mellitus 2 development. Because of the limited reports describing the effect of irisin on inflammation and immunocompetent cells activation, the present study attempted to assess the influence of various irisin concentrations on basic macrophage activity. MAIN METHODS:Studies were carried out on murine RAW 264.7 macrophages cultured in medium enriched with irisin (0nM, 10nM, 50nM, or 100nM). General cell activity, viability, and proliferation were assessed along with phagocytosis process, and respiratory burst generation. KEY FINDING:Irisin level positively correlates with general cell activity and cell cycle progression as well as with phagocytosis intensity, but negatively correlates with the intensity of respiratory burst generation. No influence of irisin on quiescent cell viability, including apoptosis or necrosis, was observed. SIGNIFICANCE:This research is the first to show that irisin modulates macrophage activity by reducing reactive oxygen species (ROS) overproduction, which could suggest its potential anti-inflammatory properties. Therefore, further studies are needed for the evaluation of influence of irisin on immunocompetent cell function. 10.1016/j.lfs.2017.03.011
    Irisin-mediated protective effect on LPS-induced acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells. Shao Lei,Meng Di,Yang Fei,Song Haibo,Tang Dongqi Biochemical and biophysical research communications It is considered that the essence of acute lung injury (ALI) is an excessive and uncontrolled inflammatory response in lung, of which mainly is attributed to the release of inflammatory mediators. Recent studies demonstrated that irisin, which is a metabolism associated factor after physical exercise could suppression of inflammation by regulating cellular signaling pathways, however, the underlying molecular mechanism remains to be determined. The present study aimed to reveal the potential mechanism responsible for the anti-inflammatory effects of irisin on LPS-induced acute lung injury in mice and in A549 cells. The results of histopathological changes showed that irisin ameliorated the lung injury that was induced by LPS in time- and dose-dependent manner. QRT-PCR assays demonstrated that irisin suppressed the production of IL-1β, IL-6, MCP-1 and TNF-α, and western blot assays demonstrated that irisin suppressed apoptosis of ALI. The expression of caspase-3 and Bax were decreased and Bcl-2 was increased by irisin administration. Further study was conducted on nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) using pathways using western blots. The results showed that irisin inhibited reduced LPS-induced activation of MAPK and NF-κB signaling. All results indicated that irisin has protective effect on LPS-induced ALI in mice and in A549 cells. Thus, irisn related with physical exercise may be a potential therapy for the treatment of pulmonary inflammation. 10.1016/j.bbrc.2017.04.020
    [Irisin as a new marker for the early diagnosis of low-traumatic fractures in rheumatoid arthritis.] Lavrova D P,Zavodovsky B V,Akhverdyan Yu R,Polyakova Yu V,Sivordova L E,Zborovskaya I A,Yakovlev A T Klinicheskaia laboratornaia diagnostika The aim of this study was to study the relationship between serum irisin level and the presence of low-traumatic bone fractures in rheumatoid arthritis (RA) patients. We examined 170 people including 110 RA patients and 60 healthy individuals as comparison group. The serum irisin level was determined with solid-phase enzyme-linked immunosorbent assay using ELISA Irisin test system (BioVendor, cat. No. RAG018R). The average level of irisin in the group of healthy individuals was 20.49 ± 4.82 μg/ml (μ±σ). The level of normal values, defined as M ± 2σ, was 10.85-30.13 μg/ml. Decreased irisin level was detected in 41 of 110 patients with RA diagnosis (37% of cases). This group of patients had higher RA activity degree (DAS28), extra-articular manifestations, disease duration from 5 to 10 years, greater class of functional joint's failure, lower level of 25 (OH) -vitamin D. There was also a reliable relationship between serum irisin level and presence of low-fracture bone fractures in the anamnesis. 10.18821/0869-2084-2018-63-11-702-706
    Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions. Zhang Dan,Xie Ting,Leung Po Sing Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:Islet metabolic disorder and inflammation contribute to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Irisin is a recently identified adipomyokine with protective effects on metabolic homeostasis and inflammation-suppressing effects in hepatic and vascular cells. The present study examined the effects of irisin on lipid metabolism and inflammation in β cells under glucolipotoxic conditions. METHODS:Rat INS-1E β cells and islets isolated from C57BL/6 mice were incubated in glucolipotoxic conditions with or without irisin. Intracellular lipid contents and lipogenic gene expression were determined by enzymatic colorimetric assays and real-time PCR, respectively. Inflammatory status was evidenced by Western blot analysis for the phosphorylation of nuclear factor-κB (NF-κB) p65 and real-time PCR analysis for the expression of pro-inflammatory genes. RESULTS:Irisin reversed glucolipotoxicity-induced intracellular non-esterified fatty acid (NEFA) and triglyceride accumulation, suppressed associated elevations in lipogenic gene expression, and phosphorylated acetyl-CoA-carboxylase (ACC) in INS-1E cells. These demonstrated effects were dependent on irisin-activated adenosine monophosphate-activated protein kinase (AMPK). Meanwhile, AMPK signaling mediated the protective effects of irisin on INS-1E cell insulin secretory ability and survival as well. Additionally, irisin inhibited phosphorylation of NF-κB p65 while decreasing the expression of pro-inflammatory genes in INS-1E cells under glucolipotoxic conditions. Moreover, irisin also improved insulin secretion, inhibited apoptosis, and restored β-cell function-related gene expression in isolated mouse islets under glucolipotoxic conditions. CONCLUSION:Irisin attenuated excessive lipogenesis in INS-1E cells under glucolipotoxic state through activation of AMPK. Irisin also suppressed overnutrition-induced inflammation in INS-1E cells. Our findings implicate irisin as a promising therapeutic target for the treatment of islet lipid metabolic disorder and islet inflammation in T2DM. 10.1159/000495395
    Irisin protects against neuronal injury induced by oxygen-glucose deprivation in part depends on the inhibition of ROS-NLRP3 inflammatory signaling pathway. Peng Juan,Deng Xian,Huang Wei,Yu Ji-Hua,Wang Jian-Xiong,Wang Jie-Ping,Yang Shi-Bin,Liu Xi,Wang Li,Zhang Yun,Zhou Xiang-Yu,Yang Hui,He Yan-Zheng,Xu Fang-Yuan Molecular immunology Recent studies found that irisin, a newly discovered skeletal muscle-derived myokine during exercise, is also synthesized in various tissues of different species and protects against neuronal injury in cerebral ischemia. The NOD-like receptor pyrin 3 (NLRP3) inflammasome play an important role in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury during ischemic stroke. However, it is unclear whether irisin is involved in the regulation of NLRP3 inflammasome activation during ischemic stroke. In the present study, PC12 neuronal cells were exposed to oxygen-glucose deprivation (OGD), exogenous irisin (12.5, 25, 50nmol/L) or NLRP3 inhibitor glyburide (50, 100, 200μmol/L) were used as an intervention reagent, NLRP3 was over-expressed or suppressed by transfection with a NLRP3 expressing vector or NLRP3-specifc siRNA, respectively. Our data showed that both irisin and its precursor protein fibronectin type III domain containing 5 (FNDC5) expression were significantly down-regulated (p<0.05); but oxidative stress and ROS-NLRP3 inflammasome signaling were activated by OGD (p<0.05); treatment with irisin or inhibition of NLRP3 reversed OGD-induced oxidative stress and inflammation (p<0.05). However, these irisin-mediated effects were blunted by over-expression NLRP3 (p<0.05). Taken together, our results firstly revealed that irisin mitigated OGD-induced neuronal injury in part via inhibiting ROS-NLRP3 inflammatory signaling pathway, suggesting a likely mechanism for irisin-induced therapeutic effect in ischemic stroke. 10.1016/j.molimm.2017.09.014
    Irisin protects macrophages from oxidized low density lipoprotein-induced apoptosis by inhibiting the endoplasmic reticulum stress pathway. Zheng Guanlin,Li Haizhen,Zhang Tie,Yang Libo,Yao Shutong,Chen Shihong,Zheng Maochuan,Zhao Qin,Tian Hua Saudi journal of biological sciences Irisin is a newly discovered myokine which can relieve metabolic disorders and resist atherosclerosis. The effects of irisin on ox-LDL-induced macrophage apoptosis and endoplasmic reticulum stress-related pathways were observed . RAW264.7 macrophages were cultured and pretreated with irisin at 20, 40 and 80 ng/ml for 30 min, followed by culture with 100 mg/L ox-LDL and 5 mg/L tunicamycin (TM) for 12 h. The cell viability and apoptosis were detected by MTT assay and annexin V-FITC double staining. The nuclear translocation of activating transcription factor 6 (ATF6) was detected by immunofluorescence assay. Western blot was used to detect the expressions of p-PERK, p-eIF2α, C/EBP homologous protein (CHOP) and Bcl-2. Irisin reduced lipid accumulation in macrophages in a concentration-dependent pattern and significantly inhibited apoptosis induced by ox-LDL and TM. Compared with ox-LDL and TM groups, the expressions of CHOP, p-PERK and p-eIF2α in the irisin group significantly decreased, the translocation of ATF6 from cytoplasm to nucleus was significantly weakened, and Bcl-2 expression significantly increased. Irisin can alleviate the apoptosis of macrophages induced by ox-LDL, which may be achieved by inhibiting the PERK/eIF2α/CHOP and ATF6/CHOP endoplasmic reticulum stress signaling pathways. 10.1016/j.sjbs.2017.08.018
    Irisin Alleviates Advanced Glycation End Products-Induced Inflammation and Endothelial Dysfunction via Inhibiting ROS-NLRP3 Inflammasome Signaling. Deng Xian,Huang Wei,Peng Juan,Zhu Ting-Ting,Sun Xiao-Lei,Zhou Xiang-Yu,Yang Hui,Xiong Jian-Feng,He Hu-Qiang,Xu You-Hua,He Yan-Zheng Inflammation The activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome have been implicated in the initiation or progression of atherosclerosis. Recent research showed that irisin, a newly discovered adipomiokine, alleviates endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses, suggesting that irisin may be a promising candidate for the treatment of vascular complications of diabetes. However, the association between irisin and NLRP3 inflammasome in the pathogenesis of atherosclerosis remains unclear. In the present study, we cultured human umbilical vein endothelial cells (HUVECs) in advanced glycation end products (AGEs) medium; exogenous irisin (0.01, 0.1, 1 μg/ml) were used as an intervention reagent. siRNA and adenoviral vector were constructed to realize silencing and over-expression of NLRP3 gene. Our data showed that irisin significantly reversed AGEs-induced oxidative stress and NLRP3 inflammasome signaling activation (p < 0.05), and increased the endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production in a dose-dependent manner (p < 0.05). siRNA-mediated knockdown NLRP3 facilitated the irisin-mediated anti-inflammatory and antiatherogenic effects (p < 0.05). However, these irisin-mediated effects were reversed by over-expression NLRP3 (p < 0.05). Taken together, our results reveal that irisin alleviates AGEs-induced inflammation and endothelial dysfunction via inhibiting ROS-NLRP3 inflammasome signaling, suggest a likely mechanism for irisin-induced therapeutic effect in vascular complications of diabetes. 10.1007/s10753-017-0685-3
    A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: An introductory review. Askari Hassan,Rajani Sulail Fatima,Poorebrahim Mansour,Haghi-Aminjan Hamed,Raeis-Abdollahi Ehsan,Abdollahi Mohammad Pharmacological research Irisin is a hormone-like molecule mainly released by skeletal muscles in response to exercise. Irisin induces browning of the white adipose tissue and has been shown to regulate glucose and lipid homeostasis. Keeping its energy expenditure and metabolic properties in view, numerous studies have focused on its therapeutic potential for the treatment of metabolic disorders like obesity and type 2 diabetes. Recently, the anti-inflammatory, anti-apoptotic and anti-oxidative properties of irisin have received a great deal of attention of the scientific society. These pathogenic processes are often associated with initiation, progression, and prognosis of numerous diseases like myocardial infarction, kidney diseases, cancer, lung injury, inflammatory bowel diseases, atherosclerosis, liver diseases, obesity and type 2 diabetes. In the current review, we present evidence regarding the anti-inflammatory, anti-apoptotic and anti-oxidative potential of irisin pertaining to various pathological conditions. Here, we explore multiple molecular pathways targeted by irisin therapy. Given the promising effects of irisin, many diseases with evident oxidative stress, inflammation and apoptosis can be targeted by irisin. 10.1016/j.phrs.2018.01.012
    Exercise Ameliorates Emphysema Of Cigarette Smoke-Induced COPD In Mice Through The Exercise-Irisin-Nrf2 Axis. Kubo Hiroaki,Asai Kazuhisa,Kojima Kazuya,Sugitani Arata,Kyomoto Yohkoh,Okamoto Atsuko,Yamada Kazuhiro,Ijiri Naoki,Watanabe Tetsuya,Hirata Kazuto,Kawaguchi Tomoya International journal of chronic obstructive pulmonary disease Background:Oxidative stress is one of the important mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD). Irisin is a type of myokine secreted from the muscle during exercise and acts against oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor with antioxidant properties. Here, we examined the emphysema suppressive effects of the exercise-irisin-Nrf2 axis in mice. Methods:Mice were divided into three groups, namely, the control, smoking, and exercise + smoking groups. All mice from the smoking and exercise + smoking groups were exposed to cigarette smoke once a day. The mice from the exercise + smoking group were adapted to a treadmill once a day. To investigate the Nrf2 cascade, after 12 weeks, serum irisin concentration and Nrf2 and heme oxygenase-1 (HO-1) expression in the lung homogenate were determined. To evaluate cigarette smoke-induced COPD, the number of inflammatory cells in bronchoalveolar lavage fluid (BALF), mean linear intercept (MLI), and destructive index in the lung tissue were examined. Results:Serum irisin concentration and the expression levels of Nrf2 and HO-1 in the lung homogenate were significantly higher in mice from the exercise + smoking group than in those from the control and smoking groups. The proportion of neutrophils in the BALF was significantly lower in the exercise + smoking group than in the smoking group. The MLI and destructive index were also significantly smaller in mice from the exercise + smoking group than mice from the smoking group. Conclusion:Irisin secreted from the muscle during exercise may exert protective effects against oxidative stress via Nrf2 and HO-1, and ameliorate emphysema of cigarette smoke-induced COPD. The exercise-irisin-Nrf2 axis may serve as a novel target for COPD treatment. 10.2147/COPD.S226623
    Irisin attenuates oxidized low-density lipoprotein impaired angiogenesis through AKT/mTOR/S6K1/Nrf2 pathway. Zhang Min,Xu Yinjie,Jiang Li Journal of cellular physiology It is known that irisin increases total body energy expenditure, decreases body weight, and enhances insulin sensitivity. Although previous studies have demonstrated that irisin induces vascular endothelial cell (EC) angiogenesis, the molecular mechanisms underlying irisin-induced angiogenesis under conditions reflecting atherosclerosis are not known. The aim of the present study is to investigate whether irisin could inhibit oxidized low-density lipoprotein (oxLDL) impaired angiogenesis. We investigated the effect of irisin on angiogenesis in vitro by evaluating cell viability, cell migration, and the capacity to form capillary-like tubes using human umbilical vein endothelial cells and human microvascular endothelial cells (HUVECs and HMEC-1) that were treated with oxLDL. We also evaluated the effects of irisin on angiogenesis in vivo by Matrigel plug angiogenesis assay and in a chicken embryo membrane (CAM) model. Our results demonstrated that irisin increased oxLDL-treated EC viability as well as migration and tube formation. Moreover, oxLDL inhibited angiogenic response in vivo, both in the Matrigel plug angiogenesis assay and in the CAM model, and was attenuated by irisin. Furthermore, irisin decreased apoptosis, inflammatory cytokines, and intracellular reactive oxygen species (ROS) levels in oxLDL-treated EC. In addition, we found that irisin upregulated pAkt/mTOR/Nrf2 in oxLDL-treated EC. Both mTOR/Nrf2 shRNA and LY294002 could inhibit the protective effect of irisin. Taken together these results, they suggested that irisin attenuates oxLDL-induced vascular injury by activating the Akt/mTOR/Nrf2 pathway. Our findings suggest that irisin attenuates oxLDL-induced blood vessel injury. 10.1002/jcp.28535
    Irisin pretreatment ameliorates intestinal ischemia/reperfusion injury in mice through activation of the Nrf2 pathway. Du Juan,Fan Xin,Yang Bo,Chen Ye,Liu Ke-Xuan,Zhou Jun International immunopharmacology Intestinal ischemia/reperfusion (I/R) injury is a serious clinical event that may induce intestinal mucosal injury, whose major underlying mechanisms include reactive oxygen species (ROS) generation, release of inflammatory mediators and induction of apoptosis. Irisin is considered an agent with potent protection against many pathological injures. The aim of this study was to investigate the protective effect of irisin pretreatment on intestinal injury and explore its underlying mechanisms in a mouse model of intestinal I/R injury as well as a cell model (IEC-6 cell) of hypoxia/reoxygenation (H/R). The results showed that irisin pretreatment ameliorated I/R and H/R-induced injury in vivo and in vitro. In addition, irisin reduced the levels of tumor necrosis factor (TNF)-α, interleukin(IL)-1β and interleukin(IL)-6 in the intestine. Compared with the I/R group, irisin pretreatment effectively reduced malondialdehyde (MDA) and myeloperoxidase (MPO) levels, but increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the intestine, and significantly reduced oxidative stress. Furthermore, irisin pretreatment downregulated Bax and cleaved Caspase-3 at the protein level, and increased Bcl-2 protein amounts, significantly reducing apoptosis in the intestine of I/R mice. Moreover, both in vivo and in vitro results showed that irisin pretreatment significantly upregulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein. Meanwhile, Nrf2 siRNA treatment partially abrogated the protective effects of irisin pretreatment on H/R induced cellular damage, inflammatory response, oxidative stress, and apoptosis in IEC-6 cells. These findings suggest that irisin pretreatment improves I/R-induced intestinal inflammatory response, reduces oxidative stress and inhibits apoptosis, which could be, at least partially, associated with Nrf2 pathway activation. 10.1016/j.intimp.2019.05.011
    Irisin alleviates pulmonary epithelial barrier dysfunction in sepsis-induced acute lung injury via activation of AMPK/SIRT1 pathways. Li Xinyi,Jamal Muhammad,Guo Peipei,Jin Zhao,Zheng Feng,Song Xuemin,Zhan Jia,Wu Huisheng Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie OBJECTIVE:Alveolar epithelial barrier dysfunction in response to inflammatory reaction contributes to pulmonary edema in acute lung injury(ALI).Irisin,a newly-found myokine,exerts the anti-inflammatory effects. This study aims to investigate the protective effects of irisin on lipopolysaccharide (LPS)-induced ALIin vivo and in vitro, and to explore its underlying mechanism. METHODS:Male SD rats and A549 cells were divided into 4 groups: control group, LPS group, Irisin pretreated group, and Irisin/Compound C(a special inhibitor of AMPK)-treated group. The ALI model was established by intravenous injection of LPS in rats, and LPS challenge in A549 cells. Pulmonary specimens were harvested for microscopic examination of the pathological changes, and the expression of AMPK,SIRT1,NF-κB, p66Shc and caspase-3 in lung tissues. The pulmonary permeability were examined by wet/dry lung weight ratio(W/D) and lung permeability index(LPI). The apoptotic index, and the expression of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), monocyte chemoattractant activating protein-1 (MCP-1), tight junctions (occludin,ZO-1) were determined both in lung tissue and A549 cells. RESULTS:Irisin alleviated lung histological changes and decreased pulmonary microvascular permeability in LPS-induced rats. Irisin up-regulated the expression of occludin, ZO-1,AMPK,SIRT1, down-regulated the expression of TNF-α,IL-1β,MCP-1,NF-κB, p66Shc caspase-3, and decreased the apoptotic index in LPS-induced rats and A549 cells. All these protective effects of irisin could be reversed by Compound C. CONCLUSION:Irisin improved LPS-induced alveolar epithelial barrier dysfunction via suppressing inflammation and apoptosis, and this protective effect might be mediated by activating AMPK/SIRT1 pathways. 10.1016/j.biopha.2019.109363