scholarly journals Substantial Dysregulation of miRNA Passenger Strands Underlies the Vascular Response to Injury

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 83 ◽  
Author(s):  
Karine Pinel ◽  
Louise Diver ◽  
Katie White ◽  
Robert McDonald ◽  
Andrew Baker
Keyword(s):  
Growth Factor ◽  
Signaling Cascades ◽  
Cytokine Signaling ◽  
Vascular Response ◽  
Vein Grafts ◽  
Individual Mirnas ◽  
Vessel Injury ◽  
Non Coding Rnas

Vascular smooth muscle cell (VSMC) dedifferentiation is a common feature of vascular disorders leading to pro-migratory and proliferative phenotypes, a process induced through growth factor and cytokine signaling cascades. Recently, many studies have demonstrated that small non-coding RNAs (miRNAs) can induce phenotypic effects on VSMCs in response to vessel injury. However, most studies have focused on the contribution of individual miRNAs. Our study aimed to conduct a detailed and unbiased analysis of both guide and passenger miRNA expression in vascular cells in vitro and disease models in vivo. We analyzed 100 miRNA stem loops by TaqMan Low Density Array (TLDA) from primary VSMCs in vitro. Intriguingly, we found that a larger proportion of the passenger strands was significantly dysregulated compared to the guide strands after exposure to pathological stimuli, such as platelet-derived growth factor (PDGF) and IL-1α. Similar findings were observed in response to injury in porcine vein grafts and stent models in vivo. In these studies, we reveal that the miRNA passenger strands are predominantly dysregulated in response to vascular injury.

125 BISPHENOL A-INDUCED GROWTH OF OVARIAN CANCER CELLS WAS REVERSED BY A PHYTOESTROGEN, GENISTEIN, BY INHIBITION OF A CROSSTALK BETWEEN ESTROGEN RECEPTOR AND INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR IN IN VITRO AND XENOGRAFT MOUSE MODELS

2014 ◽  
Vol 26 (1) ◽  
pp. 176
Author(s):  
K.-A. Hwang ◽  
S.-H. Kim ◽  
K.-C. Choi
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Mouse Model ◽  
Tumour Growth ◽  
Corn Oil ◽  
Signaling Cascades ◽  
Ovarian Cancer Cells ◽  
In Vitro Experiments

It has been shown that oestrogen (E2) up-regulated the expression of components of insulin-like growth factor-1 (IGF-1) signaling pathway and induced the downstream of mitogenic signaling cascades via phosphorylation of insulin receptor substrate-1 (IRS-1). An interaction between oestrogen receptor (ER) and IGF-1 receptor (IGF-1R) signaling pathway plays an important role in proliferation of and resistance to endocrine therapy to oestrogen-dependent cancers (i.e. breast and endometrial cancers). In the present study, we evaluated xenoestrogenic effect of bisphenol A (BPA) and antiproliferative activity of genistein (GEN) in accordance with the influence on this crosstalk. The gene expressions in mRNA and protein levels were examined by semiquantitative RT-PCR and Western blot analysis, in which the primers for ERα, IGF-1R, and GAPDH and the antibodies against pIRS-1, pAkt, and GAPDH were used, respectively. Total RNA and protein samples were isolated from BG-1 cells treated with dimethyl sulfoxide (DMSO), estradiol (E2; 10–9 M), BPA (10–5 M), E2 (10–9 M) + GEN (10–4 M), and BPA (10–5 M) + GEN (10–4 M). The DMSO was used a vehicle of E2, BPA, and GEN in in vitro experiments. All in vitro experiments were done in triplicates. The effects on tumour growth and immunohistologic alterations were identified in in vivo mouse models. The mice were injected subcutaneously with corn oil (vehicle, n = 6), E2 (n = 6), BPA (n = 6), E2+GEN (n = 6), and BPA+GEN (n = 6) for 8 weeks. The BPA treatment resulted in up-regulation of ERα and IGF-1R mRNA, and induced phosphorylation of IRS-1 and Akt proteins compared with a control (DMSO) in BG-1 ovarian cancer cells as E2 did in triplicates. In the mouse model xenografted with BG-1 cells, BPA significantly increased a tumour burden of mice and expressions of ERα, pIRS-1, and cyclin D1 in tumour mass compared with the vehicle (corn oil), indicating that BPA induces ovarian cancer growth by promoting the crosstalk between ER and IGF-1R signals. On the other hand, GEN effectively reversed estrogenicity of BPA by reversing mRNA and protein expressions of ERα, IGF-1R, pIRS-1, and pAkt induced by BPA in cellular model with triplicates. The GEN also significantly decreased tumour growth and in vivo expressions of ERα, pIRS-1, and pAkt in a xenografted mouse model. Also, GEN was confirmed to have an antiproliferative effect by inducing apoptotic signaling cascades. Taken together, these results suggest that GEN effectively reversed the increased proliferation of BG-1 ovarian cancer by suppressing the crosstalk between ER and IGF-1R signaling pathways up-regulated by BPA or E2. This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ009599), Rural Development Administration, Republic of Korea.

scholarly journals Dynamic changes of podocytes caused by fibroblast growth factor 2 in culture

2021 ◽  
Author(s):  
Eishin Yaoita ◽  
Masaaki Nameta ◽  
Yutaka Yoshida ◽  
Hidehiko Fujinaka
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 2 ◽  
Quiescent State ◽  
Fibroblast Growth ◽  
Gene Expressions ◽  
Dynamic Changes ◽  
Ki 67

AbstractFibroblast growth factor 2 (FGF2) augments podocyte injury, which induces glomerulosclerosis, although the mechanisms remain obscure. In this study, we investigated the effects of FGF2 on cultured podocytes with interdigitating cell processes in rats. After 48 h incubation with FGF2 dynamic changes in the shape of primary processes and cell bodies of podocytes resulted in the loss of interdigitation, which was clearly shown by time-lapse photography. FGF2 reduced the gene expressions of constituents of the slit diaphragm, inflections of intercellular junctions positive for nephrin, and the width of the intercellular space. Immunostaining for the proliferation marker Ki-67 was rarely seen and weakly stained in the control without FGF2, whereas intensely stained cells were frequently found in the presence of FGF2. Binucleation and cell division were also observed, although no significant increase in cell number was shown. An in vitro scratch assay revealed that FGF2 enhanced migration of podocytes. These findings show that FGF2 makes podocytes to transition from the quiescent state into the cell cycle and change their morphology due to enhanced motility, and that the culture system in this study is useful for analyzing the pathological changes of podocytes in vivo.

scholarly journals A study of deregulated MMR pathways and anticancer potential of curcuma derivatives using computational approach

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Priyanjali Bhattacharya ◽  
Trupti N. Patel
Keyword(s):  
Mismatch Repair ◽  
Protein Function ◽  
Curcuma Longa ◽  
Signaling Cascades ◽  
Altered Expression ◽  
Anticancer Properties ◽  
Medicinal Properties ◽  
Multiple Signaling

AbstractPlant derived products have steadily gained momentum in treatment of cancer over the past decades. Curcuma and its derivatives, in particular, have diverse medicinal properties including anticancer potential with proven safety as supported by numerous in vivo and in vitro studies. A defective Mis-Match Repair (MMR) is implicated in solid tumors but its role in haematologic malignancies is not keenly studied and the current literature suggests that it is limited. Nonetheless, there are multiple pathways interjecting the mismatch repair proteins in haematologic cancers that may have a direct or indirect implication in progression of the disease. Here, through computational analysis, we target proteins that are involved in rewiring of multiple signaling cascades via altered expression in cancer using various curcuma derivatives (Curcuma longa L. and Curcuma caesia Roxb.) which in turn, profoundly controls MMR protein function. These biomolecules were screened to identify their efficacy on selected targets (in blood-related cancers); aberrations of which adversely impacted mismatch repair machinery. The study revealed that of the 536 compounds screened, six of them may have the potential to regulate the expression of identified targets and thus revive the MMR function preventing genomic instability. These results reveal that there may be potential plant derived biomolecules that may have anticancer properties against the tumors driven by deregulated MMR-pathways.

scholarly journals Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samir Sissaoui ◽  
Stuart Egginton ◽  
Ling Ting ◽  
Asif Ahmed ◽  
Peter W. Hewett
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Endothelial Dysfunction ◽  
Akt Activation ◽  
Forkhead Box ◽  
Pi3k Activity ◽  
Binding Sequence

AbstractPlacenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.

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