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Zhao Yang Department of Anatomy, School of Applied Chemistry and Biological Technology, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, 212 Greene Hall, Auburn, Alabama 36849, USA

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Zhi-Li Huang Department of Anatomy, School of Applied Chemistry and Biological Technology, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, 212 Greene Hall, Auburn, Alabama 36849, USA
Department of Anatomy, School of Applied Chemistry and Biological Technology, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, 212 Greene Hall, Auburn, Alabama 36849, USA

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Ya-Xiong Tao Department of Anatomy, School of Applied Chemistry and Biological Technology, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, 212 Greene Hall, Auburn, Alabama 36849, USA

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The melanocortin-3 receptor (MC3R) is a member of the family A G protein-coupled receptors (GPCRs). The MC3R remains the most enigmatic of the melanocortin receptors with regard to its physiological functions, especially its role in energy homeostasis. The N/DPxxY motif and the eighth helix (helix 8) in the carboxyl terminus of GPCRs have been identified to be important for receptor expression, ligand binding, signal transduction and internalization. To gain a better understanding of the structure-function relationship of MC3R, we performed a systematic study of all 20 residues in this domain using alanine-scanning mutagenesis. We showed that although all mutants were expressed normally on the cell surface, eleven residues were important for ligand binding and one was indispensable for downstream cAMP generation. F347A showed constitutive activity in cAMP signaling while all the other mutants had normal basal activities. We studied the signaling capacity of nine mutants in the ERK1/2 signaling pathway. All of these mutants showed normal basal ERK1/2 phosphorylation levels. The pERK1/2 levels of six binding- or signaling-defective mutants were enhanced upon agonist stimulation. The unbalanced cAMP and pERK1/2 signaling pathways suggested the existence of biased signaling in MC3R mutants. In summary, we showed that the DPLIY motif and helix 8 was important for MC3R activation and signal transduction. Our data led to a better understanding of the structure-function relationship of MC3R.

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Qianqian Lu The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

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Yuying Yang Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Sheng Jia Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Shaoqiang Zhao Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Bin Gu Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Peng Lu The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

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Yang He Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Ruixin Liu Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Jiqiu Wang Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Guang Ning The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Qinyun Ma Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine (SJTUSM), Shanghai, China

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Appetite is tightly controlled by neural and hormonal signals in animals. In general, steroid receptor coactivator 1 (SRC1) enhances steroid hormone signalling in energy balance and serves as a common coactivator of several steroid receptors, such as oestrogen and glucocorticoid receptors. However, the key roles of SRC1 in energy balance remain largely unknown. We first confirmed that SRC1 is abundantly expressed in the hypothalamic arcuate nucleus (ARC), which is a critical centre for regulating feeding and energy balance; it is further co-localised with agouti-related protein and proopiomelanocortin neurons in the arcuate nucleus. Interestingly, local SRC1 expression changes with the transition between sufficiency and deficiency of food supply. To identify its direct role in appetite regulation, we repressed SRC1 expression in the hypothalamic ARC using lentivirus shRNA and found that SRC1 deficiency significantly promoted food intake and body weight gain, particularly in mice fed with a high-fat diet. We also found the activation of the AMP-activated protein kinase (AMPK) signalling pathway due to SRC1 deficiency. Thus, our results suggest that SRC1 in the ARC regulates appetite and body weight and that AMPK signalling is involved in this process. We believe that our study results have important implications for recognising the overlapping and integrating effects of several steroid hormones/receptors on accurate appetite regulation in future studies.

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Xilin Yang Department of Otorhinolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China

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Zezhang Tao Department of Otorhinolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China

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Zhanyong Zhu Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, China

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Hua Liao Department of Otorhinolaryngology - Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China

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Yueqiang Zhao Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, China

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Huajun Fan Department of Plastic Surgery, Renmin Hospital of Wuhan University, Wuhan, China

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Insulin plays an important role in the regulation of glucose metabolism. However, the molecular mechanisms involved are not entirely clarified. In this context, we found that miR-593-3p negatively regulates insulin-regulated glucose metabolism in hepatocellular carcinoma HepG2 and Bel7402 cells. We then identified Slc38a1 and CLIP3 as novel targets of miR-593-3p. Further studies demonstrated that Slc38a1 and CLIP3 mediate insulin-regulated glucose metabolism. Interestingly, we also demonstrated that miR-593-3p expression was negatively associated with Slc38a1 and CLIP3 expression in insulin-treated HepG2 cells, and insulin-induced Slc38a1 and CLIP3 expression via downregulation of miR-593-3p. Taken together, this study indicates that inhibition of miRNA-593-3p by insulin promotes glucose metabolism through the regulation of Slc38a1 and CLIP3 expression, and provides a new insight into the role and mechanism of insulin-induced glycolysis.

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Xiaojing Wei Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Yutian Tan Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Jiaqi Huang Institute of Basic Medicine, School of Medicine, Tsinghua University, Beijing, China

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Ximing Dong Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Weijie Feng Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Tanglin Liu Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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Zhao Yang Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

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Guiying Yang Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

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Xiao Luo Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi’an Jiaotong University, Xi’an, China
Institute of Neuroscience, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China

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N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays antidiabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in a gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with a high-fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, MNAM supplementation reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. The NAD+/sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was diminished in placenta by MNAM. In addition, weight of placenta, fetus weight, and litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of glucose tolerance tests by MNAM. Our data provide evidence for the careful usage of MNAM in treatment of GDM.

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Qianqian Lu Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China
The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

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Yuying Yang Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

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Sheng Jia Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

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Shaoqian Zhao Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

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Bin Gu Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

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Peng Lu Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China
The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

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Yang He Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

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Ruixin Liu Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

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Jiqiu Wang Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

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Guang Ning Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China
The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

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Qinyun Ma Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China

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He-jun Zhao Department of Endocrinology, Tianjin First Central Hospital, Tianjin, China

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Xia Jiang Department of Endocrinology, Tianjin First Central Hospital, Tianjin, China

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Li-juan Hu Laboratory of Acute Abdomen Disease, Tianjin NanKai Hospital, Tianjin, China

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Lei Yang Clinical Laboratory, Tianjin First Central Hospital, Tianjin, China

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Lian-dong Deng Department of Polymer Science and Technology, School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, China

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Ya-ping Wang Department of Polymer Science and Technology, School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, China

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Zhi-peng Ren Department of Orthopaedics, Tianjin Hospital, Tianjin, China

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This study aimed to determine whether and how the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide affects the chemoresistance and chemosensitivity of pancreatic cancer cells to gemcitabine in vitro and in vivo. The GLP-1R and protein kinase A (PKA) levels were compared between the human pancreatic cancer cell line PANC-1 and the gemcitabine-resistant cell line PANC-GR. The in vitro effects of liraglutide on the cell proliferation and apoptosis as well as the nuclear factor-kappa B NF-κB expression levels of PANC-GR cells were evaluated. In addition, a mouse xenograft model of human pancreatic cancer was established by s.c. injection of PANC-1 cells, and the effects of liraglutide on the chemosensitivity were evaluated in vitro and in vivo. In contrast to PANC-1 cells, PANC-GR cells exhibited lower expression levels of GLP-1R and PKA. Incubation with liraglutide dose dependently inhibited the growth, promoted the apoptosis, and increased the expression of GLP-1R and PKA of PANC-GR cells. Similar effects of liraglutide were observed in another human pancreatic cancer cell line MiaPaCa-2/MiaPaCa-2-GR. Either the GLP-1R antagonist Ex-9, the PKA inhibitor H89, or the NF-κB activator lipopolysaccharide (LPS) could abolish the antiproliferative and proapoptotic activities of liraglutide. Additionally, each of these agents could reverse the expression of NF-κB and ABCG2, which was decreased by liraglutide treatment. Furthermore, liraglutide treatment increased the chemosensitivity of pancreatic cancer cells to gemcitabine, as evidenced by in vitro and in vivo experiments. Thus, GLP-1R agonists are safe and beneficial for patients complicated with pancreatic cancer and diabetes, especially for gemcitabine-resistant pancreatic cancer.

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Yachao Zhang Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Science, Shandong Normal University, Ji’nan, Shandong, China

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Jieqiong Yang Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China

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Shijian Lv Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China

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Dong-Qin Zhao Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Science, Shandong Normal University, Ji’nan, Shandong, China

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Zi-Jiang Chen Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China

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Wei-Ping Li Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China

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Cong Zhang Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
Key Laboratory of Animal Resistance Biology of Shandong Province, College of Life Science, Shandong Normal University, Ji’nan, Shandong, China

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Preeclampsia (PE) is a pregnancy-induced disorder characterized by hypertension and proteinuria after 20 weeks of gestation, affecting 5–7% of pregnancies worldwide. So far, the etiology of PE remains poorly understood. Abnormal decidualization is thought to contribute to the development of PE. SP1 belongs to the Sp/KLF superfamily and can recruit P300 to regulate the transcription of several genes. SP1 is also very important for decidualization as it enhances the expression of tissue factor. In this study, we investigated the expression of SP1 and P300 in deciduae and their relationship with PE. A total of 42 decidua samples were collected, of which 21 were from normal pregnant (NP) and 21 from severe PE. SP1 and P300 expression in deciduae and the levels of SP1 and P300 in cultured human endometrial stromal cells (hESCs) and primary hESCs during decidualization were determined. To further investigate the role of SP1 and P300 in human decidualization, RNA interference was used to silence SP1 and P300 in hESCs and primary hESCs. The following results were obtained. We found that the expressions of SP1 and P300 were reduced in decidual tissues with PE compared to those from NP. In the in vitro model of induction of decidualization, we found an increase in both SP1 and P300 levels. Silencing of SP1 and P300 resulted in abnormal decidualization and a significant reduction of decidualization markers such as insulin-like growth factor-binding protein1 and prolactin. Furthermore, the expression of vascular endothelial growth factor was also decreased upon SP1 and P300 silencing. Similar results were observed in primary hESCs. Our results suggest that SP1 and P300 play an important role during decidualization. Dysfunction of SP1 and P300 leads to impaired decidualization and might contribute to PE.

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Ying Chen College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Hua Ni College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Xing-Hong Ma College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Shi-Jun Hu College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Li-Ming Luan College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Gang Ren College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Yue-Chao Zhao College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Shi-Jie Li College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Hong-Lu Diao College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Xiu Xu College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Zhen-Ao Zhao College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Zeng-Ming Yang College of Life Sciences, Northeast Agricultural University, Harbin 150030, China

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Although implantation types differ between species, the interaction between blastocyst trophectoderm and apical surface of the uterine epithelium is a common event during the implantation process. In this study, uterine luminal epithelium at implantation and inter-implantation sites was isolated by enzymatic digestion and used for microarray analysis. In a mouse microarray containing 12 345 unigenes, we found 136 genes upregulated more than twofold at the implantation site, while 223 genes were downregulated by at least twofold. Reverse transcription-PCR was used to verify the differential expression of seven upregulated and six downregulated genes chosen randomly from our microarray analysis, and the expression trends were similar. The differential expression patterns of eight upregulated genes were verified by in situ hybridization. Compared with the inter-implantation site on day 5 of pregnancy and the uterus on day 5 of pseudopregnancy, protease, serine, 12 neurotrypsin, endothelin-1, γ-glutamyl hydrolase, Ras homolog gene family, member U, T-cell immunoglobulin, and mucin domain containing 2, proline–serine–threonine phosphatase-interacting protein 2, 3-monooxgenase/tryptophan 5-monooxgenase activation protein, γ-polypeptide, and cysteine-rich protein 61 (Cyr61) were upregulated in the luminal epithelium at implantation site on day 5 of pregnancy. These genes may be related to embryo apposition and adhesion during embryo implantation. Cyr61, a gene upregulated at the implantation site, was chosen to examine its expression and regulation during the periimplantation period by in situ hybridization. Cyr61 mRNA was specifically localized in the luminal epithelium surrounding the implanting blastocyst at day 4 midnight and on day 5 of pregnancy, and in the activated uterus, but not expressed in inter-implantation sites and under delayed implantation, suggesting a role for Cyr61 in mediating embryonic–uterine dialog during embryo attachment. Our data could be a valuable source for future study on embryo implantation.

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He Jiang State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Xiao-Ping Ye State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Zhong-Yin Yang State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Ming Zhan State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Hai-Ning Wang State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Huang-Min Cao State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Hui-Jun Xie State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Chun-Ming Pan State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Huai-Dong Song State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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Shuang-Xia Zhao State Key Laboratory of Medical Genomics, Department of General Surgery, Shanghai Institute of Endocrinology and Metabolism, Molecular Medicine Center

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There is a high incidence of metabolic syndrome among patients with primary aldosteronism (PA), which has recently been associated with an unfavorable cardiometabolic profile. However, the underlying mechanisms have not been clarified in detail. Characterizing aldosterone (Ald) target genes in adipocytes will help us to elucidate the deleterious effects associated with excess Ald. Apelin, a novel adipokine, exerts beneficial effects on obesity-associated disorders and cardiovascular homeostasis. The objective of this study was to investigate the effects of high Ald levels on apelin expression and secretion and the underlying mechanisms involved in adipocytes. In vivo, a single-dose Ald injection acutely decreased apelin serum levels and adipose tissue apelin production, which demonstrates a clear inverse relationship between the levels of plasma Ald and plasma apelin. Experiments using 3T3-L1 adipocytes showed that Ald decreased apelin expression and secretion in a time- and dose-dependent manner. This effect was reversed by glucocorticoid receptor (GR) antagonists or GR (NR3C1) knockdown; furthermore, putative HREs were identified in the apelin promoter. Subsequently, we verified that both glucocorticoids and mineralocorticoids regulated apelin expression through GR activation, although no synergistic effect was observed. Additionally, detailed potential mechanisms involved a p38 MAPK signaling pathway. In conclusion, our findings strengthen the fact that there is a direct interaction between Ald and apelin in adipocytes, which has important implications for hyperaldosteronism or PA-associated cardiometabolic syndrome and hoists apelin on the list of potent therapeutic targets for PA.

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