FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Wrann Christiane D Brain plasticity (Amsterdam, Netherlands) Exercise can improve cognitive function and the outcome of neurodegenerative diseases, like Alzheimer's disease. This effect has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Recently, we have reported a PGC-1α-FNDC5/irisin pathway, which is activated by exercise in the hippocampus in mice and induces a neuroprotective gene program, including . This review will focus on FNDC5 and its secreted form "irisin", a newly discovered myokine, and their role in the nervous system and its therapeutic potential. In addition, we will briefly discuss the role of other exercise-induced myokines on positive brain effects. 10.3233/BPL-150019
    Effects of exercise on Irisin, BDNF and IL-6 serum levels in patients with progressive multiple sclerosis. Briken Sven,Rosenkranz Sina Cathérine,Keminer Oliver,Patra Stefan,Ketels Gesche,Heesen Christoph,Hellweg Rainer,Pless Ole,Schulz Karl-Heinz,Gold Stefan M Journal of neuroimmunology BACKGROUND:Clinical studies have suggested beneficial effects of exercise on cognitive function in ageing adults and neurodegenerative diseases such as dementia. Recent work indicates the same for progressive multiple sclerosis (MS), an inflammatory and degenerative disease of the central nervous system (CNS). The biological pathways associated with these effects are however not well understood. OBJECTIVE:In this randomized controlled study, we explored serum levels of the myokine Irisin, the neurotrophin brain-derived neurotrophic factor (BDNF) and Interleukin-6 (IL-6) during acute endurance exercise and over the course of a 9-weeks endurance exercise training period in n=42 patients with progressive MS. RESULTS:We detected a significant increase of BDNF levels in progressive MS patients after 30min of bicycling (p<0.001). However, there were no significant changes for baseline levels after 22 sessions of training. No significant effects of acute or prolonged exercise could be found for Irisin or Interleukin-6. CONCLUSION:Our results indicate that BDNF is strongly induced during acute exercise even in patients with progressive MS and advanced physical disability. Long-term effects of exercise programs on biological parameters (Irisin, BDNF, IL-6) were much less pronounced. Given the hypothesis-driven selection of a limited set of biological markers in this pilot study, future studies should use unbiased approaches in larger samples to obtain a comprehensive picture of the networks involved in exercise effects on neurological diseases. 10.1016/j.jneuroim.2016.08.007
    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
    Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Moon Hyun-Seuk,Dincer Fadime,Mantzoros Christos S Metabolism: clinical and experimental AIMS/HYPOTHESIS:Irisin is a novel, myocyte secreted, hormone that has been proposed to mediate the beneficial effects of exercise on metabolism. Irisin is expressed, at lower levels, in human brains and knock-down of the precursor of irisin, FNDC5, decreases neural differentiation of mouse embryonic stem cells. No previous studies have evaluated whether irisin may directly regulate hippocampal neurogenesis in mouse hippocampal neuronal (HN) cells. METHODS:Hippocampal neurogenesis and irisin signaling were studied in vitro using mouse H19-7 HN cell lines. RESULTS:We observed that cell proliferation is regulated by irisin in a dose-dependent manner in mouse H19-7 HN cells. Specifically, physiological concentrations of irisin, 5 to 10nmol/L, had no effect on cell proliferation when compared to control. By contrast, pharmacological concentrations of irisin, 50 to 100nmol/L, increased cell proliferation when compared to control. Similar to these results regarding irisin's effects on cell proliferation, we also observed that only pharmacological concentrations of irisin increased STAT3, but not AMPK and/or ERK, activation. Finally, we observed that irisin did not activate either microtubule-associated protein 2, a specific neurite outgrowth marker, or Synapsin, a specific synaptogenesis marker in mouse H19-7 HN cells. CONCLUSIONS/INTERPRETATIONS:Our data suggest that irisin, in pharmacological concentrations, increases cell proliferation in mouse H19-7 HN cells via STAT3, but not AMPK and/or ERK, signaling pathways. By contrast, neither physiological nor pharmacological concentrations of irisin alter markers of hippocampal neurogenesis in mouse H19-7 HN cell lines. 10.1016/j.metabol.2013.04.007
    Effect of carnosine, methylprednisolone and their combined application on irisin levels in the plasma and brain of rats with acute spinal cord injury. Albayrak Serdal,Atci İbrahim Burak,Kalayci Mehmet,Yilmaz Musa,Kuloglu Tuncay,Aydin Suna,Kom Mustafa,Ayden Omer,Aydin Suleyman Neuropeptides Spinal cord injury (SCI) might occur to anybody at any time and any age. In its treatment, methylprednisolone (MP) is a first choice worldwide, but there is still no significant breakthrough in truly beneficial treatment due to SCI's complex pathophysiology. We investigated the effect of carnosine, methylprednisolone (MP) and its combination on irisin levels in the plasma, brain and medulla spinalis tissues in SCI using a rat model. The rats were divided into 6 groups: I (Control, saline); II (sham animals with laminectomy without cross-clamping); III (SCI); IV (SCI treated with 150mg/kg carnosine); V (SCI treated with 30mg/kg methylprednisolone); and VI (SCI treated with a combination of carnosine and MP). The animals were given traumatic SCI after laminectomy, using 70-g closing force aneurysm clips (Yasargil FE 721). Irisin concentration was measured by ELISA. The distribution of irisin in brain and spinal cord tissues was examined by immunochemistry. Irisin was mainly expressed in the astrocytes and microglia of brain tissues, and multipolar neurones of the anterior horn of spinal cord tissue in rats of all groups, indicating that irisin is physiologically indispensable. MP and carnosine and the combination of the two, significantly increased irisin in plasma and were accompanied by a significant rise in irisin immunoreactivity of brain and spinal cord tissues of the injured rats compared with control and sham. This finding raises the possibility that methylprednisolone and carnosine regulate the brain and spinal cord tissues in SCI by inducing irisin expression, and may therefore offer a better neurological prognosis. 10.1016/j.npep.2015.06.004
    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
    Irisin Attenuates Neuroinflammation and Prevents the Memory and Cognitive Deterioration in Streptozotocin-Induced Diabetic Mice. Wang Kexin,Song Feng,Xu Kai,Liu Zhi,Han Shuhong,Li Fangna,Sun Yu Mediators of inflammation Diabetes mellitus (DM) patients experience memory and cognitive deficits. The mechanisms underlying this dysfunction in the brain of DM patients are not fully understood, and therefore, no optimized therapeutic strategy has been established so far. The aim of the present study was to assess whether irisin was able to improve memory and cognitive performance in a streptozotocin-induced diabetic mouse model. A diabetic mouse model was established and behavioral tests were performed. We also set up primary cultures for mechanism studies. Western blots and EMSA were used for molecular studies. Significant impairment of cognition and memory was observed in these DM mice, which could be effectively prevented by irisin cotreatment. We also found upregulated levels of GFAP protein, reduced synaptic protein expression, and increased levels of interleukin-1 (IL-1) and interleukin-6 (IL-6) in the brains; however, irisin significantly attenuated these cellular responses. Meanwhile, our results demonstrated that irisin inhibited the activation of P38, STAT3, and NFB proteins of DM mice. Furthermore, our results suggested that irisin might regulate the function of P38, STAT3, and NFB in hippocampal tissues of DM mice. Collectively, irisin inhibited neuroinflammation in STZ-induced DM mice by inhibiting cytokine release and improving their cognitive function. Our findings revealed the mechanism of irisin's anti-inflammatory effect in the CNS. 10.1155/2019/1567179
    Irisin ameliorates depressive-like behaviors in rats by regulating energy metabolism. Wang Sisi,Pan Jiyang Biochemical and biophysical research communications Depression is a common psychiatric disorder that affects millions of people around the world, however, little is known about the pathophysiology of depression and the therapeutic strategy for anti-depression. In this study, we investigated the role of irisin, a regulator of energy metabolism, in the modulation of depressive-like behaviors in chronic unpredictable stress (CUS) exposed rats. ELISA showed that irisin was aberrantly regulated by CUS in the prefrontal cortex tissues and cerebrospinal fluid (CSF) of rats. CUS-induced behavioral deficits in rats were reversed by injection treatment with recombinant irisin in a dose dependent manner. Treatment with irisin at concentrations of 100 ng/ml or higher significantly increased the sucrose preference and reduced the immobility time in CUS rats. Additionally, irisin treatment also increased the activities of mitochondrial complexes I, II and IV as well as creatine kinase, which were inhibited by CUS in the prefrontal cortex of rats. We then confirmed that irisin significantly increased the levels of glucose transport and phosphorylation, as reflected by the increased type I and type II hexokinase (Hx-1 and Hx-2) and GLUT-4 as well as the ATP level in vivo and vitro. Further studies indicated that AMPK pathway was involved in the regulation of irisin on depressive-like behaviors in CUS rats. In conclusion, we demonstrated that irisin has a crucial role in inducing antidepressant-like effects in CUS rats by regulating energy metabolism in the prefrontal cortex of brain, which may provide a new insight into the biological mechanism of depression. 10.1016/j.bbrc.2016.04.047
    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
    Molecular and Functional Interaction of the Myokine Irisin with Physical Exercise and Alzheimer's Disease. Jin Yunho,Sumsuzzman Dewan Md,Choi Jeonghyun,Kang Hyunbon,Lee Sang-Rae,Hong Yonggeun Molecules (Basel, Switzerland) Irisin, a skeletal muscle-secreted myokine, produced in response to physical exercise, has protective functions in both the central and the peripheral nervous systems, including the regulation of brain-derived neurotrophic factors. In particular, irisin is capable of protecting hippocampus. Since this area is the region of the brain that is most susceptible to Alzheimer's disease (AD), such beneficial effect may inhibit or delay the emergence of neurodegenerative diseases, including AD. Also, the factors engaged in irisin formation appear to suppress Aβ aggregation, which is the pathological hallmark of AD. This review is based on the hypothesis that irisin produced by physical exercise helps to control AD progression. Herein, we describe the physiology of irisin and its potential role in delaying or preventing AD progression in human. 10.3390/molecules23123229
    Alteration of the irisin-brain-derived neurotrophic factor axis contributes to disturbance of mood in COPD patients. Papp Csaba,Pak Krisztian,Erdei Tamas,Juhasz Bela,Seres Ildiko,Szentpéteri Anita,Kardos Laszlo,Szilasi Maria,Gesztelyi Rudolf,Zsuga Judit International journal of chronic obstructive pulmonary disease COPD is accompanied by limited physical activity, worse quality of life, and increased prevalence of depression. A possible link between COPD and depression may be irisin, a myokine, expression of which in the skeletal muscle and brain positively correlates with physical activity. Irisin enhances the synthesis of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in reward-related processes. Thus, we hypothesized that mood disturbances accompanying COPD are reflected by the changes in the irisin-BDNF axis. Case history, routine laboratory parameters, serum irisin and BDNF levels, pulmonary function, and disease-specific quality of life, measured by St George's Respiratory Questionnaire (SGRQ), were determined in a cohort of COPD patients (n=74). Simple and then multiple linear regression were used to evaluate the data. We found that mood disturbances are associated with lower serum irisin levels (SGRQ's Impacts score and reciprocal of irisin showed a strong positive association; β: 419.97; 95% confidence interval [CI]: 204.31, 635.63; <0.001). This association was even stronger among patients in the lower 50% of BDNF levels (β: 434.11; 95% CI: 166.17, 702.05; =0.002), while it became weaker for patients in the higher 50% of BDNF concentrations (β: 373.49; 95% CI: -74.91, 821.88; =0.1). These results suggest that irisin exerts beneficial effect on mood in COPD patients, possibly by inducing the expression of BDNF in brain areas associated with reward-related processes involved in by depression. Future interventional studies targeting the irisin-BDNF axis (eg, endurance training) are needed to further support this notion. 10.2147/COPD.S135701
    The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia. Li Dong-Jie,Li Yong-Hua,Yuan Hong-Bin,Qu Le-Feng,Wang Pei Metabolism: clinical and experimental BACKGROUND:Irisin is a novel exercise-induced myokine involved in the regulation of adipose browning and thermogenesis. In this study, we investigated the potential role of irisin in cerebral ischemia and determined whether irisin is involved in the neuroprotective effect of physical exercise in mice. MATERIALS AND METHODS:The middle cerebral artery occlusion (MCAO) model was used to produce cerebral ischemia in mice. First, the plasma irisin levels and changes in expression of the irisin precursor protein FNDC5 in skeletal muscle were determined post ischemic stroke. Second, the association between plasma irisin levels and the neurological deficit score, brain infarct volume, or plasma concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in mice with MCAO were evaluated. Third, the therapeutic effect of irisin on ischemic brain injury was evaluated in vivo and in vitro. Recombinant irisin was injected directly into the tail vein 30min after the MCAO operation, and then the effects of irisin treatment on brain infarct volume, neurological deficit, neuroinflammation, microglia activation, monocyte infiltration, oxidative stress and intracellular signaling pathway activation (Akt and ERK1/2) were measured. Irisin was also administered in cultured PC12 neuronal cells with oxygen and glucose deprivation (OGD). Finally, to assess the potential involvement of irisin in the neuroprotection of physical exercise, mice were exercised for 2weeks and an irisin neutralizing antibody was injected into these mice to block irisin 1h before the MCAO operation. RESULTS:The plasma irisin concentration and intramuscular FNDC5 protein expression decreased after ischemic stroke. Plasma irisin levels were negatively associated with brain infarct volume, the neurological deficit score, plasma TNF-α and plasma IL-6 concentrations. In OGD neuronal cells, irisin protected against cell injury. In mice with MCAO, irisin treatment reduced the brain infarct volume, neurological deficits, brain edema and the decline in body weight. Irisin treatment inhibited activation of Iba-1 microglia, infiltration of MPO-1 monocytes and expression of both TNF-α and IL-6 mRNA. Irisin significantly suppressed the levels of nitrotyrosine, superoxide anion and 4-hydroxynonenal (4-HNE) in peri-infarct brain tissues. Irisin treatment increased Akt and ERK1/2 phosphorylation, while blockade of Akt and ERK1/2 by specific inhibitors reduced the neuroprotective effects of irisin. Finally, the exercised mice injected with irisin neutralizing antibody displayed more severe neuronal injury than the exercised mice injected with control IgG. CONCLUSION:Irisin reduces ischemia-induced neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotective effect of physical exercise against cerebral ischemia, suggesting that irisin may be a factor linking metabolism and cardio-cerebrovascular diseases. 10.1016/j.metabol.2016.12.003
    The effects of intracerebroventricular infusion of irisin on feeding behaviour in rats. Tekin Suat,Erden Yavuz,Ozyalin Fatma,Cigremis Yilmaz,Colak Cemil,Sandal Suleyman Neuroscience letters Irisin, a novel exercise-induced myokine, has attracted attention with its effects on energy metabolism. This study was conducted to determine the possible effects of irisin on nutritional behaviour. In this study, 40 male Wistar Albino rats were separated into 4 groups (n=10 for each group). Osmotic mini-pumps were connected to metal cannulas implanted to lateral ventricle; and artificial cerebrospinal fluid (vehicle), and 10 and 100nM of irisin was infused for 7days. The daily food and water consumptions and body weights of rats were followed up. After the infusion, the animals were killed, and the hypothalamus and blood samples were collected. NPY, POMC, and UCP2 mRNA levels in the hypothalamus were examined by RT-PCR. In serum, leptin and ghrelin levels as well as the levels of metabolic parameters were measured by using ELISA. It was determined that irisin administration increased the daily food consumption (p<0.05), without causing significant changes in water consumption and body weight. Irisin also caused increases in ghrelin level in circulation and NPY and UCP2 mRNA levels in the hypothalamus, whereas it decreased the leptin level in circulation and POMC mRNA levels in the hypothalamus (p<0.05). Otherwise, irisin caused decrease in LDL, triglycerides and cholesterol levels, while increasing HDL and glucose levels (p<0.05). Results indicates that long-term irisin treatment increases food intake without increasing body weight associated with increased ghrelin, NPY and UCP2 mRNAs, and decreased leptin and POMC mRNA in the hypothalamus. 10.1016/j.neulet.2017.02.066
    Irisin Peptide Protects Brain Against Ischemic Injury Through Reducing Apoptosis and Enhancing BDNF in a Rodent Model of Stroke. Asadi Yasin,Gorjipour Fazel,Behrouzifar Sedigheh,Vakili Abedin Neurochemical research Evidence has shown therapeutic potential of irisin in cerebral stroke. The present study aimed to assess the effects of recombinant irisin on the infarct size, neurological outcomes, blood-brain barrier (BBB) permeability, apoptosis and brain-derived neurotrophic factor (BDNF) expression in a mouse model of stroke. Transient focal cerebral ischemia was established by middle cerebral artery occlusion (MCAO) for 45 min and followed reperfusion for 23 h in mice. Recombinant irisin was administrated at doses of 0.1, 0.5, 2.5, 7.5, and 15 µg/kg, intracerebroventricularly (ICV), on the MCAO beginning. Neurological outcomes, infarct size, brain edema and BBB permeability were evaluated by modified neurological severity score (mNSS), 2,3,5-triphenyltetrazolium chloride (TTC) staining and Evans blue (EB) extravasation methods, respectively, at 24 h after ischemia. Apoptotic cells and BDNF protein were detected by TUNEL assay and immunohistochemistry techniques. The levels of Bcl-2, Bax and caspase-3 proteins were measured by immunoblotting technique. ICV irisin administration at doses of 0.5, 2.5, 7.5 and 15 µg/kg, significantly reduced infarct size, whereas only in 7.5 and 15 µg/kg improved neurological outcome (P < 0.001). Treatment with irisin (7.5 µg/kg) reduced brain edema (P < 0.001) without changing BBB permeability (P > 0.05). Additionally, irisin (7.5 µg/kg) significantly diminished apoptotic cells and increased BDNF immunoreactivity in the ischemic brain cortex (P < 0.004). Irisin administration significantly downregulated the Bax and caspase-3 expression and upregulated the Bcl-2 protein. The present study indicated that irisin attenuates brain damage via reducing apoptosis and increasing BDNF protein of brain cortex in the experimental model of stroke in mice. 10.1007/s11064-018-2569-9
    The effect of intrathecal injection of irisin on pain threshold and expression rate of GABAB receptors in peripheral neuropathic pain model. Dameni Sima,Janzadeh Atousa,Yousefifard Mahmoud,Nasirinezhad Farinaz Journal of chemical neuroanatomy BACKGROUND:and aim: Irisin is a new myokine that is secreted by myocytes during exercise, and plays a role in creating the beneficial effects of exercise on metabolism. Considering the benefits of exercise in reducing pain, this study was carried out to determine the probable effect of irisin on neuropathic pain in the chronic constriction injury (CCI) model in male rats. METHODS:To induce neuropathic pain CCI model was used. Animals were divided into groups of control, CCI, sham, CCI + vehicle, and CCI + irisin. Animals that had undergone CCI were divided into 6 groups and each received a different intrathecal dose of irisin (30, 10, 3, 1, 0.3, and 0.1 μg/kg) via intrathecal administration. To evaluate the chronic effect of irisin, its effective dose was injected for 14 days in another group of animals. At the end of the experiment, animals were ranscardially perfused and their spinal cord tissue was prepared for immunohistochemical and hematoxylin-eosin staining. RESULTS:The results showed that in acute intrathecal injection of irisin, 1 μg/kg dose has the highest analgesic effect compared to other doses. Nevertheless, in chronic administration of irisin with 1 μg/kg dose, no analgesic effect was detected. In addition, irisin administration could not increase the expression level of GABAB1 and B2 or prevent the decline in the number of neurons. CONCLUSION:The findings of the present study showed that acute administration of Irisin increases the pain threshold, but the chronic injection of resin does not have an effect on pain reduction and the expression of GABA receptors and it seems that this peptide is not a proper replacement for exercise in patients with neuropathic pain, who cannot exercise. 10.1016/j.jchemneu.2018.02.010
    Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice. Siteneski Aline,Cunha Mauricio P,Lieberknecht Vicente,Pazini Francis L,Gruhn Karen,Brocardo Patricia S,Rodrigues Ana Lúcia S Progress in neuro-psychopharmacology & biological psychiatry Evidence has indicated that the practice of physical exercise has antidepressant effects that might be associated with irisin release and BDNF signaling. In this study we investigated the effects of the central administration of irisin or BDNF in predictive tests of antidepressant properties paralleled with the gene expression of peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex of mice. Irisin (0.5-1 ng/mouse, i.c.v.) reduced the immobility time in the tail suspension test (TST) and forced swim test (FST), without altering locomotion in the open field test (OFT). Irisin reduced the immobility time in the TST up to 6 h after its administration. Irisin administration (6 h) increased PGC-1α mRNA in the hippocampus and prefrontal cortex and reduced (1 h) PGC-1α mRNA in the prefrontal cortex. FNDC5 and BDNF mRNA expression was decreased (1 h) in both structures and remained reduced up to 6 h in the prefrontal cortex. Moreover, BDNF administered at 0.25 μg/mouse, i.c.v. (1 and 6 h before the test) reduced the immobility time in the TST. BDNF administration reduced PGC-1α mRNA in the hippocampus (6 h) and prefrontal cortex (1 and 6 h). It also increased FNDC5 mRNA expression in the hippocampus (1 and 6 h), but reduced the expression of this gene and also BDNF mRNA in the prefrontal cortex (1 and 6 h). None of the treatments altered BDNF protein levels in both structures. In conclusion, irisin presents a behavioral antidepressant profile similar to BDNF, an effect associated with the modulation of gene expression of PGC-1α, FNDC5 and BDNF, reinforcing the pivotal role of these genes in mood regulation. 10.1016/j.pnpbp.2018.03.004
    Effects of irisin on the dysfunction of blood-brain barrier in rats after focal cerebral ischemia/reperfusion. Guo Peipei,Jin Zhao,Wu Huisheng,Li Xinyi,Ke Jianjuan,Zhang Zongze,Zhao Qiu Brain and behavior OBJECTIVE:To investigate whether irisin could protect against blood-brain barrier (BBB) dysfunction following focal cerebral ischemia/reperfusion in rats. METHODS AND MATERIALS:Seventy-two adult male Sprague Dawley rats weighing 280-320 g were randomly divided into three groups: sham operation group (S), focal cerebral ischemia/reperfusion group (FC), and irisin group (IR). Focal cerebral ischemia was induced by improved thread occlusion of right middle cerebral artery (MCAO) for 2 hr followed by reperfusion for 24 hr in rats. After 24 hr of reperfusion, the neurological evaluation was performed by the method of Longa's score. The histopathological changes were observed by HE staining. The brain water content was determined by detecting the wet weight and dry weight. The BBB permeability was assessed by fluorescence spectrophotometer and fluorescence microscopy for Evans blue (EB) extravasation. The activity and expression of matrix metalloproteinase-9 (MMP-9) in different groups were detected by immunohistochemical staining, Western blot, and gel gelatin zymography. RESULTS:After MCAO, the neurological deficit scores, the infarct volume, the brain water content, and the EB content were higher in the FC group than those in the S group (p < .05). While after irisin treatment, these indicators mentioned above were lower than those in the IR group (p < .05). Moreover, the protein expression of MMP-9 in the cortex increased significantly after MCAO, while irisin treatment could decrease the protein expression of MMP-9 in the cortex (p < .05). CONCLUSION:Our data suggest that irisin can attenuate brain damage both morphologically and functionally and protect BBB from disruption after focal cerebral ischemia/reperfusion, which is highly associated with the inhibition of the expression and activity of MMP-9 in the brain tissue. 10.1002/brb3.1425
    The Alteration of Irisin-Brain-Derived Neurotrophic Factor Axis Parallels Severity of Distress Disorder in Bronchial Asthma Patients. Szilasi Magdolna E,Pak Krisztian,Kardos Laszlo,Varga Viktoria E,Seres Ildiko,Mikaczo Angela,Fodor Andrea,Szilasi Maria,Tajti Gabor,Papp Csaba,Gesztelyi Rudolf,Zsuga Judit Frontiers in neuroscience Distress disorder (a collective term for generalized anxiety disorder and major depressive disorder) is a well-known co-morbidity of bronchial asthma. The irisin-brain-derived neurotrophic factor (BDNF) axis is a pathway that influences several neurobehavioral mechanisms involved in the pathogenesis of distress disorder. Thus, the aim of the present study was to quantify the serum irisin and BDNF concentrations in order to investigate the possible link between the irisin/BDNF axis and distress disorder in an asthma patient cohort. Data of 167 therapy-controlled asthma patients were analyzed. Demographic, anthropometric, and anamnestic data were collected, routine laboratory parameters supplemented with serum irisin and BDNF levels were determined, pulmonary function test was performed using whole-body plethysmography, and quality of life was quantified by means of the St. George's Respiratory Questionnaire (SGRQ). Correlation analysis as well as simple and multiple linear regression were used to assess the relationship between the irisin level and the Impacts score of SGRQ, which latter is indicative of the presence and severity of distress disorder. We have found a significant, positive linear relationship between the Impacts score and the reciprocal of irisin level. This association was stronger in patients whose BDNF level was higher, and it was weaker (and statistically non-significant) in patients whose BDNF level was lower. Our results indicate that higher serum irisin level together with higher serum BDNF level are associated with milder (or no) distress disorder. This finding suggests that alteration of the irisin/BDNF axis influences the presence and severity of distress disorder in asthma patients. 10.3389/fnins.2017.00653
    Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Lourenco Mychael V,Frozza Rudimar L,de Freitas Guilherme B,Zhang Hong,Kincheski Grasielle C,Ribeiro Felipe C,Gonçalves Rafaella A,Clarke Julia R,Beckman Danielle,Staniszewski Agnieszka,Berman Hanna,Guerra Lorena A,Forny-Germano Letícia,Meier Shelby,Wilcock Donna M,de Souza Jorge M,Alves-Leon Soniza,Prado Vania F,Prado Marco A M,Abisambra Jose F,Tovar-Moll Fernanda,Mattos Paulo,Arancio Ottavio,Ferreira Sergio T,De Felice Fernanda G Nature medicine Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD. 10.1038/s41591-018-0275-4
    The Role of Irisin in Alzheimer's Disease. Kim Oh Yoen,Song Juhyun Journal of clinical medicine Alzheimer's disease (AD) is characterized by progressive memory dysfunction, oxidative stress, and presence of senile plaques formed by amyloid beta (A β ) accumulation in the brain. AD is one of the most important causes of morbidity and mortality worldwide. AD has a variety of risk factors, including environmental factors, metabolic dysfunction, and genetic background. Recent research has highlighted the relationship between AD and systemic metabolic changes such as glucose and lipid imbalance and insulin resistance. Irisin, a myokine closely linked to exercise, has been associated with glucose metabolism, insulin sensitivity, and fat browning. Recent studies have suggested that irisin is involved in the process in central nervous system (CNS) such as neurogenesis and has reported the effects of irisin on AD as one of the neurodegenerative disease. Here, we review the roles of irisin with respect to AD and suggest that irisin highlight therapeutic important roles in AD. Thus, we propose that irisin could be a potential future target for ameliorating AD pathology and preventing AD onset. 10.3390/jcm7110407
    Detection and quantitation of irisin in human cerebrospinal fluid by tandem mass spectrometry. Ruan Qingwei,Zhang Limin,Ruan Jian,Zhang Xixue,Chen Jie,Ma Cheng,Yu Zhuowei Peptides The myokine irisin can cross the blood brain barrier and act as a neurokine to protect brain function during endurance exercise. However, the mechanism of transport from the blood to cerebrospinal fluid is unknown. Irisin has been detected in rodent and human brain and human cerebrospinal fluid by using commercial antibodies and enzyme linked immunosorbent assay kits. However, as human FNDC5 has an atypical translation start codon, some studies have questioned the specificity of commercial antibodies. Recently, human irisin was identified and quantitated in plasma by using mass spectrometry. We investigated whether there was irisin in human cerebrospinal fluid and an irisin concentration gradient between in human cerebrospinal fluid and paired plasma. An irisin peptide was identified and quantitated by using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. Quantitative mass spectrometry identified the presence of irisin in human cerebrospinal fluid. The internal irisin peptides were modified to the deamidated asparagine form after deglycosylation. The unmodified internal irisin peptides were not found in CSF and irisin concentration was approximately 0.26-1.86 ng/ml in men over 80 years of age with various diseases. However, the parallel reaction monitoring (PRM) elution profiles of both modified and unmodified internal irisin peptides were not found in paired plasma samples. These data unequivocally demonstrated the presence of the glycosylated form of irisin in human cerebrospinal fluid. There were significant individual differences in men over 80 years of age with diseases. However, irisin was not detected in plasma samples by using mass spectrometry. 10.1016/j.peptides.2018.03.013
    Decreased level of irisin, a skeletal muscle cell-derived myokine, is associated with post-stroke depression in the ischemic stroke population. Tu Wen-Jun,Qiu Han-Cheng,Liu Qiang,Li Xuemei,Zhao Ji-Zong,Zeng Xianwei Journal of neuroinflammation BACKGROUND:Depression is a frequent mood disorder in stroke patient. Our aim was to determine irisin levels in serum and investigate their associations with post-stroke depression (PSD) in a 6-month follow-up study in Chinese patients with first-ever acute ischemic stroke (AIS). METHODS:The subjects were first-ever AIS patients who were hospitalized at three stroke centers during the period from January 2015 to December 2016. Neurological and neuropsychological evaluations were conducted at the 6-month follow-up. Serum irisin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS:During the study period, 1205 patients were included in the analysis. There were 370 patients (30.7%) classified as depression. The depression distribution across the irisin quartiles ranged between 49.8% (first quartile) and 9.9% (fourth quartile). In the patients with depression, serum irisin levels were lower compared with those in patients without depression (P < 0.001). In a multivariate model using the first (Q1) quartile of irisin vs. Q2-4 together with the clinical variables, the marker displayed predictive information and increased risk of PSD by 75% (odds ratio [OR] for Q1, 1.75 [95% confidence interval [CI], 1.15-2.65]). In addition, a model containing known risk factors plus irisin compared with a model containing known risk factors without irisin showed a greater discriminatory ability; the area under the curve (AUC) increased from 0.77 to 0.81 (95% CI, 0.76-0.86). CONCLUSIONS:The data suggested that reduced serum levels of irisin were powerful biological markers of risk of developing PSD even after adjustment by variables. Further studies are necessary to confirm this association, which may open the way to the proposal of new therapeutic options. TRIAL REGISTRATION:ChiCTR-OPC-17013501 . Retrospectively registered 23 September 2017. 10.1186/s12974-018-1177-6
    Aquarobic exercises improve the serum blood irisin and brain-derived neurotrophic factor levels in elderly women. Kim Ji-Hyeon,Kim Do-Yeon Experimental gerontology BACKGROUND:The increase in the prevalence of degenerative brain diseases owing to the growing elderly population is becoming a serious social issue, and regular exercises can be effective in preventing and treating such diseases. Irisin, one of the myokines expressed in the muscles during exercise, is highly associated with the expression of brain-derived neurotrophic factor (BDNF). Therefore, the purpose of this study was to analyze the effect of aquarobic exercises on serum irisin and BDNF levels to help prevent and delay degenerative brain diseases in elderly women. MATERIALS AND METHODS:Twenty-six elderly women voluntarily participated in the study (12 in the control group and 14 in the exercise group). The exercise group underwent a 16-week aquarobic exercise program. The irisin and BDNF levels and liver function were measured in both groups: three times in the exercise group and two times in the control group. RESULTS:Significantly higher serum irisin (p < 0.001) and BDNF (p < 0.05) levels in the aquarobic exercise group than in the control group were found after 16 weeks of exercise, and significant interaction effects of irisin (p < 0.001) and BDNF (p < 0.01) were found in both the control and exercise groups. The serum irisin (p < 0.01 and p < 0.001, respectively) and BDNF (p < 0.05, p < 0.001, respectively) levels were significantly higher 30 min after the first exercise session and 30 min after the last exercise session in the 16th week than during the rest period before the 16 weeks of exercise. CONCLUSIONS:Aquarobic exercises were found to improve the serum irisin and BDNF levels; thus, it could be effective in preventing degenerative brain diseases and enhancing brain function of elderly women. 10.1016/j.exger.2018.01.024
    Exercise-induced myokine FNDC5/irisin functions in cardiovascular protection and intracerebral retrieval of synaptic plasticity. Zhou Xin,Xu MengMeng,Bryant Joseph L,Ma Jianjie,Xu Xuehong Cell & bioscience Physical exercise is well known to benefit human health at every age. However, the exact mechanism through which physical exercise improves health remains unknown. Recent studies into exercise-induced myokine FNDC5/irisin, a newly discovered hormone, have begun to shed light on this mystery. Exercise-induced myokine FNDC5/irisin have been shown to be protective against cardiovascular damage post ischemic event, improve function in the neurons of Alzheimer's disease patients, and have been implicated in macrophage and adipocyte regulation. Elegantly designed experiments have shown FNDC5/irisin to promote Nkx2.5 cardiac progenitor cell dependent cardiac regeneration, neovascularization, and reduce cardiac fibrosis. It has also been shown to improve macrophage function, which may protect against injuries to the cardiac conduction system. Similarly, FNDC5/irisin knockout mice have been shown to have reduced memory performance, while peripheral overexpression of FNDC5/irisin has been shown to improve memory impairment in a murine Alzheimer's disease model. Finally, FNDC5/irisin has been linked to regulation of osteocytes and adipocytes by signaling through the cytoplasmic membrane integrated protein aV/b5 integrin, the first known receptor for this newly discovered hormone. Although these recent discoveries have cemented the importance of FNDC5/irisin, many details regarding how FNDC5/irisin fits into the physiology of exercise benefits remain unknown and are deserving of future inquiry. 10.1186/s13578-019-0294-y
    Serum irisin is upregulated in patients affected by amyotrophic lateral sclerosis and correlates with functional and metabolic status. Lunetta Christian,Lizio Andrea,Tremolizzo Lucio,Ruscica Massimiliano,Macchi Chiara,Riva Nilo,Weydt Patrick,Corradi Ettore,Magni Paolo,Sansone Valeria Journal of neurology INTRODUCTION:The progression of amyotrophic lateral sclerosis (ALS) leads to a decline of the nutritional status that represents an independent prognostic factor for survival. Recent studies recognize the muscle tissue as an endocrine organ able to release several molecules, called myokines. Among them, irisin seems to be involved in the regulation of metabolism, body weight and development and function of the nervous system. OBJECTIVES:(1) To evaluate irisin serum levels in patients with ALS, with comparison to healthy subjects; (2) to assess the possible association of circulating irisin levels of ALS patients with the metabolic status, clinical and biochemical features. METHODS:We performed an observational, cross-sectional study in 50 ALS patients and 32 age- and sex-comparable healthy controls. Patients underwent to a complete set of neurological, pulmonary and nutritional evaluations. Serum irisin concentration was measured by enzyme immunoassay. According to indirect calorimetry, ALS patients were divided into a normo-metabolic patient group (n = 24) and a hyper-metabolic patient group (n = 26). RESULTS:ALS patients showed significantly higher serum irisin levels compared to healthy subjects (51.0 ± 37.8 vs 13.1 ± 2.2 ng/mL, p < 0.0001). Hyper-metabolic ALS patients displayed higher serum irisin levels compared to normo-metabolic ALS patients and healthy controls (p < 0.0009 and p < 0.0001, respectively). Serum irisin levels showed significant association with the ALSFRS-R (β=-1.18, p = 0.042), Forced Vital Capacity (β = - 0.64, p = 0.013), Fat Mass (β=-1.44, p = 0.034), pCO arterial blood levels (β = 2.67, p = 0.003), HCO arterial blood levels (β = 5.44, p = 0.001) and Free Fat Mass (β = 1.07, p = 0.025) adjusted for sex, age and metabolic status. CONCLUSIONS:ALS patients with impaired metabolic status showed higher serum irisin levels compared to normo-metabolic ALS patients and healthy subjects. Irisin levels were also negatively correlated with the extent of functional and respiratory impairment, due to as yet unknown causes, being more elevated in patients with greater disability. 10.1007/s00415-018-9093-3
    Circulating irisin and chemerin levels as predictors of seizure control in children with idiopathic epilepsy. Elhady Marwa,Youness Eman R,Gafar Heba S,Abdel Aziz Ali,Mostafa Rehab S I Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology Irisin and chemerin peptides expression are triggered by hypoxia and involved in activation of inflammatory cascades in various organs including the brain; however, their role in epilepsy is not fully illustrated. This study aims to explore the predictive role of irisin and chemerin for seizure control in children with idiopathic epilepsy. This cross-sectional comparative study included 50 children with idiopathic epilepsy; 25 of them had controlled seizures over the previous 6 months and 30 age- and sex-matched healthy children as controls. Epilepsy characteristics, seizure severity Chalfont score, and response to medications were assessed in relation to serum irisin and chemerin levels. In comparison to healthy controls, serum chemerin and irisin levels were significantly higher in children with idiopathic epilepsy especially those with uncontrolled seizures. Serum chemerin and irisin levels had significant positive correlation with seizure severity Chalfont score and the duration of epilepsy. Elevated Chalfont score (OR 3.19), serum chemerin (OR 2.01), and irisin (OR 2.03) are predictors of uncontrolled seizures. Circulating chemerin and irisin have 80% and 76% sensitivity and 88% and 92% specificity at cutoff point > 191.38 ng/ml and > 151.2 ng/ml respectively for prediction of uncontrolled seizures in children with idiopathic epilepsy. Elevated circulating level of irisin and chemerin may predict poor seizure control in children with idiopathic epilepsy suggesting the role of hypoxia-triggered neuroinflammation in the pathogenesis of childhood idiopathic epilepsy. 10.1007/s10072-018-3448-5
    Decreased Concentration of Irisin Is Associated with Poor Functional Outcome in Ischemic Stroke. Tu Wen-Jun,Qiu Han-Cheng,Cao Jian-Lei,Liu Qiang,Zeng Xian-Wei,Zhao Ji-Zong Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Irisin was discovered as a PGC-1a-activated messenger of myocytes that links sedentary lifestyle, obesity, and diabetes. In this study, we investigated the short-term prognostic value of early measurement of irisin concentration in 1530 Han Chinese patients with acute ischemic stroke (AIS) from three stroke centers. The subjects were the first-ever AIS patients who were hospitalized at three stroke centers during the period from January 2015 to December 2016. Clinical information and stroke severity were collected at admission. Neurological evaluations were conducted at the 6-month follow-up. Serum levels of irisin, National Institutes of Health Stroke Scale (NIHSS), and conventional risk factors were evaluated to determine their value to predict functional outcome and mortality within 6 months. Multivariate analyses were performed using logistic regression models. During follow-up, a poor functional outcome was found in 588 patients (38.4%; 95% confidence interval (CI), 36.0-40.9%), and 325 patients died (21.2%; 95% CI, 19.2-23.3%). The stroke patients included in the study were divided into four groups according to irisin quartiles (first is the lowest level). Poor outcome across the irisin quartiles ranged from 54.5% (first quartile) to 21.7% (fourth quartile), and mortality rate ranged from 39.3% (first quartile) to 6.3% (fourth quartile). In a multivariate model using the first quartile (Q1) of irisin vs. Q2-Q4 together with the clinical variables, the marker displayed prognostic information and increased odds ratios of poor outcome by 58% (OR for Q1, 1.58 [95% CI, 1.12-2.43]) and mortality by 185% (OR for Q1, 2.85 [95% CI, 1.79-4.02]). In addition, a model containing known risk factors plus irisin compared with a model containing known risk factors without irisin showed a greater discriminatory ability to predict poor outcome (the area under the curve (AUC) with an increase from 0.73 to 0.75 [95% CI, 0.70-0.81]) and mortality (the AUC increased from 0.80 to 0.83 [95% CI, 0.78-0.87]). Irisin is a novel, independent prognostic marker improving currently used risk stratification of stroke patients. Further studies are needed to confirm this association, which may pave the way to new therapeutic options. Trial registration: ChiCTR-OPC- 17013501. 10.1007/s13311-018-0651-2
    Altered irisin/BDNF axis parallels excessive daytime sleepiness in obstructive sleep apnea patients. More Csaba E,Papp Csaba,Harsanyi Szilvia,Gesztelyi Rudolf,Mikaczo Angela,Tajti Gabor,Kardos Laszlo,Seres Ildiko,Lorincz Hajnalka,Csapo Krisztina,Zsuga Judit Respiratory research STUDY OBJECTIVES:Obstructive sleep apnea hypopnea syndrome (OSAHS) is a sleep-related breathing disorder, characterized by excessive daytime sleepiness (EDS), paralleled by intermittent collapse of the upper airway. EDS may be the symptom of OSAHS per se but may also be due to the alteration of central circadian regulation. Irisin is a putative myokine and has been shown to induce BDNF expression in several sites of the brain. BDNF is a key factor regulating photic entrainment and consequent circadian alignment and adaptation to the environment. Therefore, we hypothesized that EDS accompanying OSAHS is reflected by alteration of irisin/BDNF axis. METHODS:Case history, routine laboratory parameters, serum irisin and BDNF levels, polysomnographic measures and Epworth Sleepiness Scale questionnaire (ESS) were performed in a cohort of OSAHS patients (n = 69). Simple and then multiple linear regression was used to evaluate data. RESULTS:We found that EDS reflected by the ESS is associated with higher serum irisin and BDNF levels; β: 1.53; CI: 0.35, 6.15; p = 0.012 and β: 0.014; CI: 0.0.005, 0.023; p = 0.02, respectively. Furthermore, influence of irisin and BDNF was significant even if the model accounted for their interaction (p = 0.006 for the terms serum irisin, serum BDNF and their interaction). Furthermore, a concentration-dependent effect of both serum irisin and BDNF was evidenced with respect to their influence on the ESS. CONCLUSIONS:These results suggest that the irisin-BDNF axis influences subjective daytime sleepiness in OSAS patients reflected by the ESS. These results further imply the possible disruption of the circadian regulation in OSAHS. Future interventional studies are needed to confirm this observation. 10.1186/s12931-019-1033-y
    Neuroprotective effects of irisin against cerebral ischemia/ reperfusion injury via Notch signaling pathway. Jin Zhao,Guo Peipei,Li Xinyi,Ke Jianjuan,Wang Yanlin,Wu Huisheng Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie Irisin, a 112-amino acid peptide induced with exercise in mice and human is thought to have correlation with the short-term outcomes of patients in ischemic stroke. In the present study, the neuroprotective effects of irisin were evaluated in vivo and in vitro and its underlying mechanism was also explored. The global cerebral ischemia/reperfusion (I/R) model was established by bilateral common carotid artery occlusion for 20 min and reperfusion for 24 h in mice and oxygen-glucose deprivation/reperfusion in HT22 cells. Neurological function was scored and then the mice were sacrificed. The brains were harvested for HE staining and detection of brain water content (BWC). The percentage of neuronal apoptosis was evaluated by TUNEL and flow cytometry analysis. The mRNA expression of TNF-α and IL-1β was detected by RT-PCR analysis. The Notch intracellular domain (NICD) was detected by double immunofluorescence staining and western blot, and the protein expression of Notch1 and Hes 1 was detected by western blot. It was observed that irisin could alleviate morphological damage and improve neurological function after global cerebral I/R injury in mice. The apoptosis of hippocampal neurons reduced in the presence of irisin in vivo and in vitro. Additionally irisin could downregulate the expression of IL-1β and TNF-α and upregulate the expression of NICD, Notch1 and Hes 1 in vitro and in vivo. After the application of γ-secretase inhibitor DAPT, all the morphological, neurological and biochemical changes were reversed. Taken together, these results suggest that irisin could regulate the Notch signaling pathway that leads to the alleviation of transient global cerebral I/R injury. 10.1016/j.biopha.2019.109452
    Serum levels of irisin predict short-term outcomes in ischemic stroke. Wu Huisheng,Guo Peipei,Jin Zhao,Li Xinyi,Yang Xin,Tang Chaoliang,Wang Yanlin,Ke Jianjuan Cytokine OBJECTIVE:Irisin is a 112-amino acid peptide found in rat and human skeletal muscle after exercise. Previous studies had suggested that higher circulating irisin levels were associated with an increased risk of vascular atherosclerosis and cardiovascular diseases. In this study, we determined irisin levels in serum, and investigated their associations with functional outcomes in a 3-month follow-up study in Chinese patients with first-ever acute ischemic stroke (AIS). METHODS:From September 2015 to December 2016, consecutive first-ever AIS patients admitted to the Department of Emergency of our hospital were identified. Serum irisin levels were measured at admission. Functional impairment was evaluated at discharge using the modified Rankin scale. The levels of irisin were expressed as median and interquartile ranges [IQR]. RESULTS:The irisin level was obtained in 324 patients (97.6%) with a median value of 291.2 ng/ml (IQR: 214.1-404.2 ng/ml). There were significantly negative correlations between levels of irisin and NHISS (r = -0.272; P < 0.001) and BMI (r = -0.193; P = 0.003). A poor functional outcome was found in 99 patients (30.6%; 95%CI: 25.5-35.6%). The poor functional outcome distribution across the irisin quartiles ranged between 51.9% (first quartile: Q1) to 12.4% (fourth quartile: Q4). In a multivariate model using the Q1 of irisin vs. Q2-4 together with the clinical variables, the marker displayed prognostic information and increased risk of poor outcomes by 94% (OR for Q1, 1.94 [95% CI, 1.19-3.42]; P = 0.018) and mortality 66% (OR for Q1, 1.66 [95% CI, 1.11-3.07]; P = 0.009). In addition, a model containing known risk factors plus irisin compared with a model containing known risk factors without irisin showed a greater discriminatory ability to predict poor outcomes (P = 0.01) and mortality (P = 0.02). CONCLUSIONS:A low serum irisin level is a predictor of poor early functional outcome in ischemic stroke patients. The underlying mechanisms of these associations remain to be investigated. 10.1016/j.cyto.2018.02.017