Dexamethasone-induced intrauterine growth restriction impacts the placental prolactin family, insulin-like growth factor-II and the Akt signaling pathway

Intrauterine growth restriction (IUGR) is a major cause of perinatal death and neonatal morbidity and mortality. There are numerous causes of IUGR. Glucocorticoid-induced IUGR is highly relevant because administration of synthetic glucocorticoids, principally dexamethasone, to women threatened by premature labor is widely used in clinical practice. Fetal growth is directly related to placental growth and development. In this report, we analyzed the effect of dexamethasone on placental development in the rat. Dexamethasone administered between days 13 and 20 of pregnancy not only induced IUGR but also decreased placental mass by approximately 50%. Impaired placental development was associated with dysregulated placental prolactin (PRL) family and insulin-like growth factor-II (IGF-II) gene expression. Furthermore, there was a significant decrease in the activation of Akt/protein kinase B in the junctional zone of the placenta, as assessed by the phosphorylation status of Akt and the pro-apoptotic protein BAD, a downstream target of the Akt signaling pathway. Such changes are consistent with increases in indices of apoptosis, including increased cleavage of poly(ADP-ribose) polymerase (PARP) in the junctional zone of the placenta of dexamethasone-treated rats. In summary, dexamethasone-induced IUGR is associated with placental insufficiency, including dysregulated placental hormone/cytokine gene expression and down-regulation of the IGF-II/Akt signaling pathway resulting in increases in indices of placental apoptosis.

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Osthole Inhibits Insulin-like Growth Factor-1-Induced Epithelial to Mesenchymal Transition via the Inhibition of PI3K/Akt Signaling Pathway in Human Brain Cancer Cells

Journal of Agricultural and Food Chemistry ◽

10.1021/jf501047g ◽

2014 ◽

Vol 62 (22) ◽

pp. 5061-5071 ◽

Cited By ~ 39

Author(s):

Ying-Chao Lin ◽

Jia-Ching Lin ◽

Chao-Ming Hung ◽

Yeh Chen ◽

Liang-Chih Liu ◽

...

Keyword(s):

Growth Factor ◽

Human Brain ◽

Cancer Cells ◽

Signaling Pathway ◽

Brain Cancer ◽

Epithelial To Mesenchymal Transition ◽

Akt Signaling ◽

Insulin Like Growth Factor ◽

Akt Signaling Pathway ◽

Mesenchymal Transition

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Knockdown of Nrf2 inhibits angiogenesis by downregulating VEGF expression through PI3K/Akt signaling pathway in cerebral microvascular endothelial cells under hypoxic conditions

Biochemistry and Cell Biology ◽

10.1139/bcb-2017-0291 ◽

2018 ◽

Vol 96 (4) ◽

pp. 475-482 ◽

Cited By ~ 17

Author(s):

Yujing Huang ◽

Ying Mao ◽

Huiying Li ◽

Guangxun Shen ◽

Guangxian Nan

Keyword(s):

Vascular Endothelial Growth Factor ◽

Ischemic Stroke ◽

Growth Factor ◽

Signaling Pathway ◽

Akt Signaling ◽

Tube Formation ◽

Vascular Endothelial ◽

Akt Signaling Pathway ◽

Microvascular Endothelial ◽

Endothelial Growth Factor

Ischemic stroke is a major cerebrovascular disease resulting from a transient or permanent local reduction of cerebral blood flow. Angiogenesis plays an important role in cerebral microvascular repair after ischemic stroke. This study aimed at investigating the effect of NF-E2-related factor 2 (Nrf2) on the angiogenesis of mouse cerebral microvascular endothelial bEnd.3 cells in a hypoxic environment. We found that Nrf2 expression was temporarily increased in hypoxia-induced bEnd.3 cells. Knockdown of Nrf2 inhibited the proliferation, migration, as well as tube formation in hypoxia-induced bEnd.3 cells. Meanwhile, vascular endothelial growth factor and PI3K/Akt signaling pathways were identified to be regulated by Nrf2 in hypoxia-induced bEnd.3 cells. It was found that silencing of Nrf2 downregulated the expression levels of NAD(P)H:quinine oxidoreductase-1, vascular endothelial growth factor, p-Akt, and heme oxygenase-1 in hypoxia-induced bEnd.3 cells. Data suggested that hypoxia induced the transient increase of Nrf2, which plays a key role in the angiogenesis of cerebral microangiogenesis, and that Nrf2 regulates the proliferation, migration, as well as tube formation likely through PI3K/Akt signaling pathway in hypoxia-induced bEnd.3 cells. Our study provides proof of concept for the modulation of Nrf2, so as to tilt the balance toward angiogenesis, representing a therapeutic strategy for hypoxia or ischemia disorders such as stroke.

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Camptothecin inhibits platelet-derived growth factor-BB-induced proliferation of rat aortic vascular smooth muscle cells through inhibition of PI3K/Akt signaling pathway

Experimental Cell Research ◽

10.1016/j.yexcr.2012.12.024 ◽

2013 ◽

Vol 319 (7) ◽

pp. 982-991 ◽

Cited By ~ 15

Author(s):

Eun-Seok Park ◽

Shin-il Kang ◽

Kyu-dong Yoo ◽

Mi-Yea Lee ◽

Hwan-Soo Yoo ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Signaling Pathway ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Akt Signaling ◽

Platelet Derived Growth Factor ◽

Akt Signaling Pathway

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Regulation of Vascular Endothelial Growth Factor Expression by EMMPRIN via the PI3K-Akt Signaling Pathway

Molecular Cancer Research ◽

10.1158/1541-7786.mcr-06-0042 ◽

2006 ◽

Vol 4 (6) ◽

pp. 371-377 ◽

Cited By ~ 79

Author(s):

Yi Tang ◽

Marian T. Nakada ◽

Patricia Rafferty ◽

Jenny Laraio ◽

Francis L. McCabe ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Signaling Pathway ◽

Akt Signaling ◽

Vascular Endothelial ◽

Akt Signaling Pathway ◽

Factor Expression ◽

Growth Factor Expression ◽

Endothelial Growth Factor

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Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00048.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. E735-E744 ◽

Cited By ~ 3

Author(s):

Mary Frances Lopez ◽

Lingyun Zheng ◽

Ji Miao ◽

Reddy Gali ◽

Grzegorz Gorski ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Growth Factor ◽

Hepatic Steatosis ◽

Intrauterine Growth Restriction ◽

Nutritional Deficiency ◽

Growth Restriction ◽

Newborn Mouse ◽

Hepatic Lipid ◽

Intrauterine Growth

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long comorbidities. Insulin-like growth factor-II (IGF2) deficiency in humans, as well as in mice, leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn. We found that, despite being born significantly smaller than their wild-type ( Igf2+/+) littermates, brain size was preserved in Igf2 knockout ( Igf2−/−), consistent with nutritional deficiency. Histological and triglyceride analyses of newborn livers revealed that Igf2−/− mice are born with hepatic steatosis. Gene expression analysis in Igf2−/− newborn livers showed an alteration of genes known to be dysregulated in chronic caloric restriction, including the most upregulated gene, serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also upregulated. Ingenuity Pathway Analysis confirmed that the biological functions most altered in livers of Igf2−/− newborns are related to lipid metabolism, with the top upstream regulator predicted to be the peroxisome proliferator-activated receptor alpha, a master regulator of hepatic lipid and carbohydrate homeostasis. Together, our data indicate that Igf2 deficiency leads to a newborn phenotype strongly reminiscent of nutritional deficiency, including growth retardation, increased brain/body weight ratio, hepatic steatosis, and characteristic changes in hepatic gene expression. We propose that in addition to its growth factor proliferating functions, Igf2 may also regulate growth by altering the expression of genes that control nutrient metabolism in the newborn.

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Insulin-like growth factor-1 induces the phosphorylation of PRAS40 via the PI3K/Akt signaling pathway in PC12 cells

Neuroscience Letters ◽

10.1016/j.neulet.2012.03.068 ◽

2012 ◽

Vol 516 (1) ◽

pp. 105-109 ◽

Cited By ~ 18

Author(s):

Haitao Wang ◽

Qishan Zhang ◽

Lang Zhang ◽

Peter J. Little ◽

Xiaochun Xie ◽

...

Keyword(s):

Growth Factor ◽

Signaling Pathway ◽

Pc12 Cells ◽

Akt Signaling ◽

Insulin Like Growth Factor ◽

Akt Signaling Pathway

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Bcl-2 Is Involved in Cardiac Hypertrophy through PI3K-Akt Pathway

BioMed Research International ◽

10.1155/2021/6615502 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Xianwei Meng ◽

Jun Cui ◽

Guibin He

Keyword(s):

Gene Expression ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Enrichment Analysis ◽

B Cell Lymphoma ◽

Akt Signaling ◽

Receptor Interaction ◽

Pathway Enrichment Analysis ◽

Akt Signaling Pathway ◽

Upregulated Genes

Cardiac hypertrophy (CH) is a common cause of sudden cardiac death and heart failure, resulting in a significant medical burden. The present study is aimed at exploring potential CH-related pathways and the key downstream effectors. The gene expression profile of GSE129090 was obtained from the Gene Expression Omnibus database (GEO), and 1325 differentially expressed genes (DEGs) were identified, including 785 upregulated genes and 540 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway enrichment analysis of DEGs were then performed. Although there were no pathways enriched by downregulated genes, many CH-related pathways were identified by upregulated genes, including PI3K-Akt signaling pathway, extracellular matrix- (ECM-) receptor interaction, regulation of actin cytoskeleton, and hypertrophic cardiomyopathy (HCM). In the deeper analysis of PI3K-Akt signaling pathway, we found all the signaling transduction pointed to B cell lymphoma-2- (Bcl-2-) mediated cell survival. We then demonstrated that PI3K-Akt signaling pathway was indeed activated in cardiac hypertrophy. Furthermore, no matter LY294002, an inhibitor of the PI3K/AKT signaling pathway, or Venetoclax, a selective Bcl-2 inhibitor, protected against cardiac hypertrophy. In conclusion, these data indicate that Bcl-2 is involved in cardiac hypertrophy as a key downstream effector of PI3K-Akt signaling pathway, suggesting a potential therapeutic target for the clinical management of cardiac hypertrophy.

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The Neuroprotective Effects of Insulin-Like Growth Factor 1 via the Hippo/YAP Signaling Pathway is Mediated by the PI3K/AKT Pathway Following Cerebral Ischemia-Reperfusion Injury

10.21203/rs.3.rs-187237/v1 ◽

2021 ◽

Author(s):

Pian Gong ◽

Yichun Zou ◽

Wei Zhang ◽

Qi Tian ◽

Shoumeng Han ◽

...

Keyword(s):

Ischemic Stroke ◽

Growth Factor ◽

Signaling Pathway ◽

Neuronal Death ◽

Infarct Volume ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Neuroprotective Effects

Abstract Insulin-like growth factor 1 (IGF-1) exhibits neuroprotective properties, such as vasodilatory and anti-inflammatory effects following ischemic stroke. However, the specific molecular mechanisms of action of IGF-1 following ischemic stroke remain elusive. We wanted to explore whether IGF-1 regulates Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT signaling pathway to exert its neuroprotective effects following ischemic stroke. In the in vitro study, we used oxygen–glucose deprivation to injure cultured PC12 and SH-5YSY cells, and cortical primary neurons. Cell viability was measured using CCK-8 assay. For the in vivo analyses, Sprague–Dawley rats were subjected to middle cerebral artery occlusion; neurological function was assessed using the neurological deficit score; infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis was evaluated by TUNEL staining, H&E staining and Nissl staining. Western blot was used to measure the levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. We found that IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and decreased neurological deficits, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were reversed by an inhibitor of the PI3K/AKT signaling pathway, LY294002, which not only reduced expressions of PI3K and p-AKT, but also down-regulated expression of YAP/TAZ, leading to aggravation of neurological dysfunction. These findings indicate that neuroprotective effect of IGF-1 is partly realized by up-regulation of YAP/TAZ, which is mediated by activation of the PI3K/AKT signaling pathway following cerebral ischemic stroke.

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