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Vijay Menon, Saghi Ghaffari
PURPOSE OF REVIEW: Work in the past decade has revealed key functions of the evolutionary conserved transcription factors Forkhead box O (FOXO) in the maintenance of homeostatic hematopoiesis. Here the diverse array of FOXO functions in normal and diseased hematopoietic stem and progenitor cells is reviewed and the main findings in the past decade are highlighted. Future work should reveal FOXO-regulated networks whose alterations contribute to hematological disorders. RECENT FINDINGS: Recent studies have identified unanticipated FOXO functions in hematopoiesis including in hematopoietic stem and progenitor cells (HSPC), erythroid cells, and immune cells...
May 17, 2018: Current Opinion in Hematology
Andrea Cerquone Perpetuini, Andrea David Re Cecconi, Michela Chiappa, Giulia Benedetta Martinelli, Claudia Fuoco, Giovanni Desiderio, Luisa Castagnoli, Cesare Gargioli, Rosanna Piccirillo, Gianni Cesareni
BACKGROUND: Skeletal muscle is characterized by an efficient regeneration potential that is often impaired during myopathies. Understanding the molecular players involved in muscle homeostasis and regeneration could help to find new therapies against muscle degenerative disorders. Previous studies revealed that the Ser/Thr kinase p21 protein-activated kinase 1 (Pak1) was specifically down-regulated in the atrophying gastrocnemius of Yoshida hepatoma-bearing rats. In this study, we evaluated the role of group I Paks during cancer-related atrophy and muscle regeneration...
May 21, 2018: Journal of Cachexia, Sarcopenia and Muscle
Valentina Grossi, Giovanna Forte, Paola Sanese, Alessia Peserico, Tugsan Tezil, Martina Lepore Signorile, Candida Fasano, Rosaura Lovaglio, Rosanna Bagnulo, Daria C Loconte, Francesco C Susca, Nicoletta Resta, Cristiano Simone
The HSF and FOXO families of transcription factors play evolutionarily conserved roles in stress resistance and lifespan. In humans, the rs2802292 G-allele at FOXO3 locus has been associated with longevity in all human populations tested; moreover, its copy number correlated with reduced frequency of age-related diseases in centenarians. At the molecular level, the intronic rs2802292 G-allele correlated with increased expression of FOXO3, suggesting that FOXO3 intron 2 may represent a regulatory region. Here we show that the 90-bp sequence around the intronic single nucleotide polymorphism rs2802292 has enhancer functions, and that the rs2802292 G-allele creates a novel HSE binding site for HSF1, which induces FOXO3 expression in response to diverse stress stimuli...
May 4, 2018: Nucleic Acids Research
Meng-Chuan Chen, Wen-Lin Hsu, Tz-Chong Chou
Skeletal muscle atrophy, the most characteristic feature of cancer cachexia, often occurs in patients with cancer undergoing chemotherapy. Antrodia cinnamomea (AC) a widely used edible medical fungus, exhibits hepatoprotective, anti-inflammatory and anticancer activities. In this study, we investigated whether combined treatment with the ethonolic extract of AC ameliorates cachexia symptoms, especially muscle wasting, in lung tumor-bearing mice treated with chemotherapy. Our results revealed that gemcitabine and cisplatin-induced severe body weight loss and skeletal muscle atrophy in the mice with cancer were greatly attenuated after AC extract administration...
April 13, 2018: Oncotarget
Hassen Kared, Serena Martelli, Shu Wen Tan, Yannick Simoni, Meng Li Chong, Siew Hwei Yap, Evan W Newell, Sylvia L F Pender, Adeeba Kamarulzaman, Reena Rajasuriar, Anis Larbi
Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions-a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection...
2018: Frontiers in Immunology
Jie Yin, Lele Yang, Yangli Xie, Yan Liu, Sheng Li, Wenjun Yang, Bo Xu, Hongbin Ji, Lianghua Ding, Kun Wang, Gang Li, Lin Chen, Ping Hu
Age-related muscle atrophy (sarcopenia) is the leading cause for disability in aged population, but the underlying molecular mechanisms are poorly understood. Here we identify a novel role for the secreted glycoprotein Dickkopf 3 (Dkk3) in sarcopenia. Forced expression of Dkk3 in muscles in young mice leads to muscle atrophy. Conversely, reducing its expression in old muscles restores both muscle size and function. Dkk3 induces nuclear import of β-catenin and enhances its interaction with FoxO3, which in turn activates the transcription of E3 ubiquitin ligase Fbxo32 and Trim63, driving muscle atrophy...
May 1, 2018: Nature Communications
Dong Guo, Ji Ma, Tengfei Li, Lei Yan
Dysfunction of the microRNA (miR) network has been emerging as a main regulator in ischemic stroke. Recently, studies have linked the deregulation of miR-122 to ischemic stroke. However, the specific role and molecular mechanism of miR-122 in ischemic stroke remain to be further investigated. Here, we found that miR-122 was decreased in mouse N2A neuroblastoma (N2A) cells after oxygen-glucose deprivation (OGD) and mouse brain after transient middle cerebral artery occlusion (MCAO). OGD treatment significantly increased N2A cell death and Caspase-3 activity, and decreased Bcl-2 protein expression...
April 28, 2018: Experimental Cell Research
Yunyuan Zhang, Liping Li, Chunjie Yu, Vitalyi Senyuk, Fuxing Li, John G Quigley, Tongyu Zhu, Zhijian Qian
MicroRNAs (miRNAs) are emerging as critical regulators of normal and malignant hematopoiesis. In previous studies of acute myeloid leukemia miR-9 overexpression was commonly observed. Here, we show that ectopic expression of miR-9 in vitro and in vivo significantly blocks differentiation of erythroid progenitor cells with an increase in reactive oxygen species (ROS) production. Consistent with this observation, ROS scavenging enzymes, including superoxide dismutase (Sod2), Catalase (Cat), and glutathine peroxidase (Gpx1), are down-regulated by miR-9...
April 25, 2018: Scientific Reports
Zikang Xie, Yuxing Qu, Pengfei Shen, Bin Wang, Kang Wei, Bin Du
The present study aimed to determine the role of transcription factor PU.1 (PU.1) in tumor necrosis factor‑α (TNF‑α)‑induced proliferation and cytokine release of rheumatoid arthritis fibroblast‑like synoviocytes (RA‑FLS). It was determined that TNF‑α induced proliferation of RA‑FLS, whereas transfection with PU.1 3'untranslated region (UTR) inhibited this proliferation. Additionally, PU.1 3'UTR attenuated TNF‑α‑induced production of interleukin (IL)‑6 and IL‑1β, and downregulated the expression level of micro RNA (miR)‑155 in a dose‑dependent manner...
April 23, 2018: Molecular Medicine Reports
Jaimin S Shah, Reem Sabouni, Kamaria C Cayton Vaught, Carter M Owen, David F Albertini, James H Segars
PURPOSE: Mammalian oogenesis and folliculogenesis share a dynamic connection that is critical for gamete development. For maintenance of quiescence or follicular activation, follicles must respond to soluble signals (growth factors and hormones) and physical stresses, including mechanical forces and osmotic shifts. Likewise, mechanical processes are involved in cortical tension and cell polarity in oocytes. Our objective was to examine the contribution and influence of biomechanical signaling in female mammalian gametogenesis...
April 24, 2018: Journal of Assisted Reproduction and Genetics
Philip M C Davy, D Craig Willcox, Michio Shimabukuro, Timothy A Donlon, Trevor Torigoe, Makoto Suzuki, Moritake Higa, Hiroaki Masuzaki, Masataka Sata, Randi Chen, Rachel Murkofsky, Brian J Morris, Eunjung Lim, Richard C Allsopp, Bradley J Willcox
FOXO3 is one of the most prominent genes demonstrating a consistently reproducible genetic association with human longevity. The mechanisms by which these individual gene variants confer greater organismal lifespan are not well understood. We assessed the effect of longevity-associated FOXO3 alleles on age-related leukocyte telomere dynamics in a cross-sectional study comprising of samples from 121 healthy Okinawan-Japanese donors aged 21-95 years. We found that telomere length for carriers of the longevity associated allele of FOXO3 single nucleotide polymorphism rs2802292 displayed no significant correlation with age, an effect that was most pronounced in older (>50) participants...
April 21, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Andrew J O'Leary, Sarah E Drummond, Deirdre Edge, Ken D O'Halloran
Oxygen deficit (hypoxia) is a major feature of cardiorespiratory diseases characterized by diaphragm dysfunction, yet the putative role of hypoxic stress as a driver of diaphragm dysfunction is understudied. We explored the cellular and functional consequences of sustained hypoxic stress in a mouse model. Adult male mice were exposed to 8 hours of normoxia, or hypoxia (FiO2  = 0.10) with or without antioxidant pretreatment (N-acetyl cysteine, 200 mg/kg i.p.). Ventilation and metabolism were measured. Diaphragm muscle contractile function, myofibre size and distribution, gene expression, protein signalling cascades, and oxidative stress (TBARS) were determined...
2018: Oxidative Medicine and Cellular Longevity
Taasin Srivastava, Parham Diba, Justin M Dean, Fatima Banine, Daniel Shaver, Matthew Hagen, Xi Gong, Weiping Su, Ben Emery, Daniel L Marks, Edward N Harris, Bruce Baggenstoss, Paul H Weigel, Larry S Sherman, Stephen A Back
Cerebral white matter injury (WMI) persistently disrupts myelin regeneration by oligodendrocyte progenitor cells (OPCs). We identified a specific bioactive hyaluronan fragment (bHAf) that downregulates myelin gene expression and chronically blocks OPC maturation and myelination via a tolerance-like mechanism that dysregulates pro-myelination signaling via AKT. Desensitization of AKT occurs via TLR4 but not TLR2 or CD44. OPC differentiation was selectively blocked by bHAf in a maturation-dependent fashion at the late OPC (preOL) stage by a noncanonical TLR4/TRIF pathway that induced persistent activation of the FoxO3 transcription factor downstream of AKT...
May 1, 2018: Journal of Clinical Investigation
See-Hyoung Park, Jongsung Lee, Jong Cheol Shon, Nguyen Minh Phuc, Jun Goo Jee, Kwang-Hyeon Liu
BACKGROUND: Broussonetia papyrifera (L.) Ventenat, a traditional medicinal herb, has been applied as a folk medicine to treat various diseases. Broussochalcone A (BCA), a chalcone compound isolated from the cortex of Broussonetia papyrifera (L.) Ventenat, exhibits several biological activities including potent anti-oxidant, antiplatelet, and cytotoxic effects. PURPOSE: The purpose of this study is to elucidate the inhibitory effect of BCA against CYP2J2 enzyme which is predominantly expressed in human tumor tissues and carcinoma cell lines...
March 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Wen Chen, Lei Zhang, Zhong-Qi Zhou, Yue-Qin Ren, Li-Na Sun, Yu-Lin Man, Zhong-Wei Ma, Zhi-Kui Wang
BACKGROUND/AIMS: Chronic renal failure (CRF) is usually associated with chronic diseases such as congestive heart failure and diabetes mellitus, the prevalence of which is increased with age. This study is designed to investigate the role of long intergenic non-coding RNA (lincRNA) LINC00963 in renal interstitial fibrosis (RIF) and oxidative stress (OS) of CRF via the forkhead box O (FoxO) signaling pathway. METHODS: Microarray data and annotated probe files related to CRF were downloaded by retrieving Gene Expression Omnibus (GEO) database to screen differentially expressed lncRNA...
March 29, 2018: Cellular Physiology and Biochemistry
Yanni Zhang, Hui Zhao, Lichuan Zhang
Circular RNAs (circRNAs) are a class of endo-genous noncoding RNAs that have been demonstrated to be potential regulators in the development and progression of various types of human cancer. However, little is known about their roles in cancer initiation and progression, particular in non‑small cell lung cancer (NSCLC). In the present study, the expression level of circRNA‑forkhead box O3 class (FOXO3) in NSCLC specimens was determined and its functional role was investigated in NSCLC cells. By performing Taq‑man based RT‑qPCR, it was identified that circRNA‑FOXO3 was downregulated in NSCLC tissues and cell lines...
March 29, 2018: Molecular Medicine Reports
Haiyan Zhang, Zhen Zhang, Surong Wang, Shiqian Zhang, Junying Bi
As a seriously global health problem, cervical cancer is a great risk to women which threatens their lives. Approximately 30% patients who received definitive treatment may fail to recover from this disease. Accordingly, there is an imperatively need to explore alternative therapeutic approaches for this disease. Several studies have revealed that miR-9 was a critical regulator during cervical cancer growth. Here, we reported that the miR-9 was overexpressed in cervical tumor tissue and exerted a promoting effect on human cervical cancer cell (SiHa) growth...
March 27, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Chang Liu, Guangyang Xing, Cailiang Wu, Jun Zhu, Min Wei, Dajiang Liu, Yan Ge, Yao Chen, Ting Lei, Yongxiu Yang
BACKGROUND The aim of this study was to investigate the expression and silencing of the S100A8 gene, which encodes the S100 calcium-binding protein A8 (S100A8), and apoptosis and phosphorylation of protein kinase B (Akt) in tissue samples of endometrial carcinoma and HEC-1A endometrial adenocarcinoma cells in vitro. MATERIAL AND METHODS Immunohistochemistry (IHC) was used to detect expression of the S100A8 protein in 74 tissue samples of endometrial cancer and 22 normal endometrial tissue samples. A stable S100A8 gene knockdown cell line was constructed using lentiviral packing short hairpin RNA (shRNA) transfected into HEC-1A cells...
March 29, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Anthony M J Sanchez, Robin Candau, Henri Bernardi
AMP-activated protein kinase (AMPK) is a critical enzyme in conditions of cellular energy deficit such as exercise, hypoxia or nutritional stress. AMPK is well known to regulate protein degradation pathways notably through FOXO-related axis. In this study, we investigated the implication of AMPK activation in FOXO3 expression and stability in skeletal muscle primary myotubes. First, time course and dose response studies revealed optimal AICAR treatment duration and dose in skeletal muscle cells. Then, experiments with cycloheximide treatment of primary myotubes highlighted that AICAR infusion extends FOXO3 protein half-life...
May 15, 2018: Biochemical and Biophysical Research Communications
Malik Bisserier, Narendra Wajapeyee
Resistance to targeted therapies has become increasingly prevalent. We noted that resistance to different targeted therapies occurs by largely common mechanisms. In this study, we used this information for identifying the mechanisms of resistance to Enhancer of Zeste Homolog 2 (EZH2) inhibitors in diffuse large B-cell lymphoma (DLBCL) harboring EZH2 mutations. We discovered that EZH2 inhibitor resistance DLBCL cells showed activation of the IGF-1R, MEK, and PI3K pathways. Constitutive activation of IGF-1R, MEK or PI3K pathways were sufficient to confer resistance to EZH2 inhibitors in DLBCL...
March 23, 2018: Blood
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