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Xiaoyang Yang Department of Physiology, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0J9

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Yan Jin Department of Physiology, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0J9

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Peter A Cattini Department of Physiology, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0J9

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Expression of pituitary and placental members of the human GH and chorionic somatomammotropin (CS) gene family is directed by an upstream remote locus control region (LCR). Pituitary-specific expression of GH requires direct binding of Pit-1 (listed as POU1F1 in the HUGO database) to sequences marked by a hypersensitive site (HS) region (HS I/II) 14.6 kb upstream of the GH-N gene (listed as GH1 in the HUGO database). We used human embryonic kidney 293 (HEK293) cells overexpressing wild-type and mutant Pit-1 proteins as a model system to gain insight into the mechanism by which Pit-1 gains access to the GH LCR. Addition of Pit-1 to these cells increased DNA accessibility at HS III, located 28 kb upstream of the human GH-N gene, in a POU homeodomain-dependent manner, as reflected by effects on histone hyperacetylation and RNA polymerase II activity. Direct binding of Pit-1 to HS III sequences is not supported. However, the potential for binding of ETS family members to this region has been demonstrated, and Pit-1 association with this ETS element in HS III sequences requires the POU homeodomain. Also, both ETS1 and ELK1 co-precipitate from human pituitary extracts using two independent sources of Pit-1 antibodies. Finally, overexpression of ELK1 or Pit-1 expression in HEK293 cells increased GH-N RNA levels. However, while ELK1 overexpression also stimulated placental CS RNA levels, the effect of Pit-1 appeared to correlate with ETS factor levels and target GH-N preferentially. These data are consistent with recruitment and an early role for Pit-1 in remodeling of the GH LCR at the constitutively open HS III through protein–protein interaction.

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Wen-Li Zhao The Key Laboratory of Plant Cell Engineering and Germplasm Innovation, Ministry of Education, Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, China

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Chun-Yan Liu The Key Laboratory of Plant Cell Engineering and Germplasm Innovation, Ministry of Education, Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, China

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Wen Liu The Key Laboratory of Plant Cell Engineering and Germplasm Innovation, Ministry of Education, Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, China

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Di Wang The Key Laboratory of Plant Cell Engineering and Germplasm Innovation, Ministry of Education, Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, China

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Jin-Xing Wang The Key Laboratory of Plant Cell Engineering and Germplasm Innovation, Ministry of Education, Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, China

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Xiao-Fan Zhao The Key Laboratory of Plant Cell Engineering and Germplasm Innovation, Ministry of Education, Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Jinan 250100, China

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Insect molting and metamorphosis are regulated by two hormones: 20-hydroxyecdysone (20E) and juvenile hormone (JH). The hormone 20E regulates gene transcription via the nuclear receptor EcR to promote metamorphosis, whereas JH regulates gene transcription via its intracellular receptor methoprene-tolerant (Met) to prevent larval–pupal transition. However, the function and mechanism of Met in various insect developments are not well understood. We propose that Met1 plays a key role in maintaining larval status not only by promoting JH-responsive gene transcription but also by repressing 20E-responsive gene transcription in the Lepidopteran insect Helicoverpa armigera. Met1 protein is increased during feeding stage and decreased during molting and metamorphic stages. Met1 is upregulated by JH III and a low concentration of 20E independently, but is downregulated by a high concentration of 20E. Knockdown of Met1 in larvae causes precocious pupation, decrease in JH pathway gene expression, and increase in 20E pathway gene expression. Met1 interacts with heat shock protein 90 and binds to JH response element to regulate Krüppel homolog 1 transcription in JH III induction. Met1 interacts with ultraspiracle protein 1 (USP1) to repress 20E transcription complex EcRB1/USP1 formation and binding to ecdysone response element. These data indicate that JH via Met1 regulates JH pathway gene expression and represses 20E pathway gene expression to maintain the larval status.

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Jin Bai Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Thomas J Lechuga Department of Biology, San Bernardino Valley College, San Bernardino, California, USA

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Joshua Makhoul Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Hao Yan Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Carol Major Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Afshan Hameed Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Dong-bao Chen Department of Obstetrics and Gynecology, University of California, Irvine, California, USA

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Elevated endogenous estrogens stimulate human uterine artery endothelial cell (hUAEC) hydrogen sulfide (H2S) production by selectively upregulating the expression of H2S synthesizing enzyme cystathionine β-synthase (CBS), but the underlying mechanisms are underdetermined. We hypothesized that CBS transcription mediates estrogen-stimulated pregnancy-dependent hUAEC H2S production. Estradiol-17β (E2β) stimulated CBS but not cystathionine γ-lyase (CSE) expression in pregnant human uterine artery ex vivo, which was attenuated by the estrogen receptor (ER) antagonist ICI 182,780. E2β stimulated CBS mRNA/protein and H2S production in primary hUAEC from nonpregnant and pregnant women, but with greater responses in pregnant state; all were blocked by ICI 182,780. Human CBS promoter contains multiple estrogen-responsive elements (EREs), including one ERE preferentially binding ERα (αERE) and three EREs preferentially binding ERβ (βERE), and one full ERE (α/βERE) and one half ERE (½α/βERE) binding both ERα and ERβ. Luciferase assays using reporter genes driven by human CBS promoter with a series of 5′-deletions identified the α/βEREs binding both ERα and ERβ (α/βERE and ½α/βERE) to be important for baseline and E2β-stimulated CBS promoter activation. E2β stimulated ERα/ERβ heterodimerization by recruiting ERα to α/βEREs and βERE, and ERβ to βERE, α/βEREs, and αERE. ERα or ERβ agonist alone trans-activated CBS promoter, stimulated CBS mRNA/protein and H2S production to levels comparable to that of E2β-stimulated, while ERα or ERβ antagonist alone abrogated E2β-stimulated responses. E2β did not change human CSE promoter activity and CSE mRNA/protein in hUAEC. Altogether, estrogen-stimulated pregnancy-dependent hUAEC H2S production occurs by selectively upregulating CBS expression via ERα/ERβ-directed gene transcription.

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Yan Jin Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada

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Jessica S Jarmasz Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada

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Shakila Sultana Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada

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Luis Cordero-Monroy Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada

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Carla G Taylor Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada
Department of Food and Human Nutritional Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

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Peter Zahradka Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Albrechtsen Research Centre, Winnipeg, Manitoba, Canada

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Elissavet Kardami Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada

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Peter A Cattini Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada

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The objective was to assess the potential differential effects of human versus mouse growth hormone in vivo, given that human unlike mouse growth hormone can bind prolactin as well as the growth hormone receptor. To this end, a transgenic CD-1 mouse expressing human but not mouse growth hormone was generated, and the phenotypes of male mice fed with a regular chow or high-fat diet were assessed. Pancreas and epididymal white adipose tissue gene expression and/or related function were targeted as the pancreas responds to both prolactin and growth hormone receptor signaling, and catabolic effects like lipolytic activity are more directly attributable to growth hormone and growth hormone receptor signaling. The resulting human growth hormone-expressing mice are smaller than wild-type CD-1 mice, despite higher body fat and larger adipocytes, but both mouse types grow at the same rate with similar bone densities. Unlike wild-type mice, there was no significant delay in glucose clearance in human growth hormone-expressing mice when assessed at 8 versus 24 weeks on a high-fat diet. However, both mouse types showed signs of hepatic steatosis that correlated with elevated prolactin but not growth hormone RNA levels. The larger adipocytes in human growth hormone-expressing mice were associated with modified leptin (higher) and adiponectin (lower) RNA levels. Thus, while limited to observations in the male, the human growth hormone-expressing mice exhibit signs of growth hormone insufficiency and adipocyte dysfunction as well as an initial resistance to the negative effects of high-fat diet on glucose clearance.

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Rubab Akbar The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Kamran Ullah The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
Department of Zoology, University of Swabi, Anbar, Khyber Pakhtunkhwa, Pakistan

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Tanzil Ur Rahman The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Yi Cheng The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Hai-Yan Pang The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Lu-Yang Jin The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Qi-Jing Wang The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
Department of Reproductive Endocrinology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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He-Feng Huang The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Jian-Zhong Sheng The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Receptive endometrium is a prerequisite for successful embryo implantation, and it follows that poor endometrial receptivity is a leading cause of implantation failure. miRNAs play important roles as epigenetic regulators of endometrial receptivity and embryo implantation through post-transcriptional modifications. However, the mechanisms of action of many miRNAs are poorly understood. In this study, we investigated the role of the miR-183 family, comprising three miRNAs (miR-183-5p, miR-182-5p, and miR-96-5p) in endometrial receptivity and embryo implantation. The miR-183 family shows estrogen-dependent upregulation in endometrial Ishikawa (IK) cells. The miR-183 family also has a positive role in migration and proliferation of IK cells. Furthermore, JAr spheroid attachment experiments show that attachment rates were significantly decreased after treatment of IK cells with inhibitors for miR-183-5p and miR-182-5p and increased after treatment with miR-183-5p-mimic and miR-96-5p-mimic, respectively. The downstream analysis shows that catenin alpha 2 (CTNNA2) is a potential target gene for miR-183-5p, and this was confirmed in luciferase reporter assays. An in vivo mouse pregnancy model shows that inhibition of miR-183-5p significantly decreases embryo implantation rates and increases CTNNA2 expression. Downregulation of CTNNA2 in endometrial cells by miR-183-5p may be significant in mediating estrogenic effects on endometrial receptivity. In conclusion, miR-183-5p and the CTNNA2 gene may be potential biomarkers for endometrial receptivity and may be useful diagnostic and therapeutic targets for successful embryo implantation.

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Kamran Ullah The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Tanzil Ur Rahman The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Hai-Tao Pan The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Shaoxing Women and Children’s Hospital, Shaoxing, Zhejiang, China

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Meng-Xi Guo The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Xin-Yan Dong The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Juan Liu The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China

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Lu-Yang Jin The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Yi Cheng The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Zhang-Hong Ke The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China

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Jun Ren The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Xian-Hua Lin The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Xiao-Xiao Qiu Department of Pathophysiology, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Ting-Ting Wang The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China

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He-Feng Huang The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Jian-Zhong Sheng The Key Laboratory of Reproductive Genetics (Zhejiang University), Ministry of Education, Hangzhou, Zhejiang, China
Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

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Previous studies have shown that increasing estradiol concentrations had a toxic effect on the embryo and were deleterious to embryo adhesion. In this study, we evaluated the physiological impact of estradiol concentrations on endometrial cells to reveal that serum estradiol levels probably targeted the endometrium in controlled ovarian hyperstimulation (COH) protocols. An attachment model of human choriocarcinoma (JAr) cell spheroids to receptive-phase endometrial epithelial cells and Ishikawa cells treated with different estradiol (10−9 M or 10−7 M) concentrations was developed. Differentially expressed protein profiling of the Ishikawa cells was performed by proteomic analysis. Estradiol at 10−7 M demonstrated a high attachment rate of JAr spheroids to the endometrial cell monolayers. Using iTRAQ coupled with LC–MS/MS, we identified 45 differentially expressed proteins containing 43 significantly upregulated and 2 downregulated proteins in Ishikawa cells treated with 10−7 M estradiol. Differential expression of C3, plasminogen and kininogen-1 by Western blot confirmed the proteomic results. C3, plasminogen and kininogen-1 localization in human receptive endometrial luminal epithelium highlighted the key proteins as possible targets for endometrial receptivity and interception. Ingenuity pathway analysis of differentially expressed proteins exhibited a variety of signaling pathways, including LXR/RXR activation pathway and acute-phase response signaling and upstream regulators (TNF, IL6, Hmgn3 and miR-140-3p) associated with endometrial receptivity. The observed estrogenic effect on differential proteome dynamics in Ishikawa cells indicates that the human endometrium is the probable target for serum estradiol levels in COH cycles. The findings are also important for future functional studies with the identified proteins that may influence embryo implantation.

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Jie Sun College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China
Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Yan Liu College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China
Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Jinhui Yu College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China
Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Shandong Center of Crop Germplasm Resources, Shandong Academy of Agricultural Sciences, Jinan, Shandong, China

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Jin Wu Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Wenting Gao Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Liyuan Ran Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Rujiao Jiang Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Meihua Guo Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Dongyu Han Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Bo Liu Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Ning Wang Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Youwei Li Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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He Huang Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China

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Li Zeng Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China

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Ying Gao Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, China

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Xin Li Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York, USA
Department of Urology of Langone Medical Center, New York University, New York, New York, USA
Perlmutter Cancer Institute of Langone Medical Center, New York University, New York, New York, USA

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Yingjie Wu College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, China
Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, Liaoning, China
National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, China
Liaoning Province Key Lab of Genetically Engineered Animal Models, Dalian Medical University, Dalian, Liaoning, China
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York, USA
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York, New York, USA

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Astragalus polysaccharide (APS) is the main component of Astragalus membranaceus, an anti-diabetic herb being used for thousands of years in Traditional Chinese medicine (TCM). In this study, we aimed to evaluate the impact of APS on hepatic insulin signaling, autophagy and ER stress response in high-fat-diet (HFD)-induced insulin resistance (IR) mice. APS was intra-gastrically administrated and metformin was used as a control medicine. Apart from monitoring the changes in the important parameters of IR progression, the gene and protein expression of the key factors marking the state of hepatic ER stress and autophagic flux were examined. We found that, largely comparable to the metformin regime, APS treatment resulted in an overall improvement of IR, as indicated by better control of body weight and blood glucose/lipid levels, recovery of liver functions and regained insulin sensitivity. In particular, the excessive and pro-apoptotic ER stress response and inhibition of autophagy, as a result of prolonged HFD exposure, were significantly corrected by APS administration, indicating a switch of the cellular fate in favor of cell survival. Using the HepG2/IR cell model, we demonstrated that APS modulated the insulin-initiated phosphorylation cascades in a similar manner to metformin. This study provides a rationale for exploiting the insulin-sensitizing potential of APS, which has a therapeutic performance almost equivalent to metformin, to enrich our options in the treatment of IR.

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