Project description:DUSP6 plays important roles in MAPK signaling pathway, but whether and how it is involved in liver funciton remains to be explored. Here, we performed RNA-seq analyses in AML12 cells where DUSP6 is disrupted. We overexpressed GFP-DUSP6 or GFP in AML12 cells, and tested the effects of DUSP6 increase on gene expression in AML12 cells. Meanwhile, we knocked down DUSP6 in AML12 cells and tested the effects of DUSP6 decrease on gene expression in AML12 cells. Taken together, we analyzed the changes of gene expression mediated by DUSP6, which provides new insights for the function of DUSP6 in liver
Project description:Irisin is a recently identified myokine that is induced by exercise and stimulates brown-fat-like development of white fat and energy expenditure in humans and mice. In this study, we aimed to evaluate the pro-proliferative effect of irisin on C2C12 myoblasts and its mechanisms of action.
Project description:Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KOs, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral administration, resulting in enrichment of central irisin, was sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.
Project description:Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KOs, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral administration, resulting in enrichment of central irisin, was sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.
Project description:Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KOs, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral administration, resulting in enrichment of central irisin, was sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.
Project description:Physical activity is thought to provide clinical benefit in Parkinson’s diseas (PD). Irisin is a blood-brain barrier permeable exercise-induced polypeptide secreted by muscle that mediates, in part, the beneficial effects of exercise. Here we show that irisin prevents pathologic -synuclein (-syn) induced neurodegeneration in the -syn preformed fibril mouse model of sporadic PD. Intravenous delivery of adenoviral irisin in vivo after the stereotaxic intrastriatal injection of -syn pre-formed fibrils reduced the formation of pathologic -syn and prevented the loss of dopamine neurons and reductions in striatal dopamine. Irisin also reduced the -syn pre-formed fibril induced motor deficits as assessed by the pole test and grip strength test. Administration of recombinant irisin in primary cortical neurons prevented pathologic -syn toxicity. Tandem mass spectrometry and biochemical analysis revealed that irisin reduced pathologic -syn by enhancing endolysosomal degradation of pathologic -syn. Our findings highlight the potential for therapeutic disease modification of irisin in PD.
Project description:Collectively, our study reveals that irisin can enhance chondrogenic differentiation of hMSCs via the Rap1/PI3K/AKT pathway, suggesting that irisin possesses prospects in cartilage regeneration. Collectively, our study reveals that irisin can enhance chondrogenic differentiation of hMSCs via the Rap1/PI3K/AKT pathway, suggesting that irisin possesses prospects in cartilage regeneration.
Project description:We identified the ubiquitin ligase Uhrf2 as an important regulator of liver regeneration. To gain insight into the mechanisms of action of Uhrf2 in hepatocytes, we searched for Uhrf2 interactors in the AML12 hepatocyte cell line using BioID interaction screening. This resulted in the identification of major chromatin remodelling proteins as Uhrf2 interactors.
Project description:Exercise benefits the human body in many ways. Irisin is secreted by muscle, increased with exercise, and conveys many physiological benefits, including improved cognition and resistance to neurodegeneration. Irisin acts via αV integrins; however, a mechanistic understanding of how small polypeptides like irisin can signal through integrins is poorly understood. Using mass spectrometry and cryo-EM, we demonstrate that extracellular heat-shock protein 90α (eHsp90α) is secreted by muscle with exercise and acts as a required cofactor that “opens” the integrin αVβ5 structure to allows for high affinity irisin binding and signaling through an eHsp90α/αV/β5 complex. By including hydrogen/deuterium exchange data, we generate and experimentally validate a 2.98 Å RMSD irisin/αVβ5 complex docking model. Irisin binds very tightly to an alternative interface on αVβ5 distinct from that involved in its interaction with known ligands. These data together elucidate a non-canonical mechanism by which a small polypeptide hormone like irisin can function through integrins.