scholarly journals Long Noncoding RNA FENDRR Inhibits Lung Fibroblast Proliferation via a Reduction of β-Catenin

2021 ◽  
Vol 22 (16) ◽  
pp. 8536
Author(s):  
Lakmini Kumari Senavirathna ◽  
Yurong Liang ◽  
Chaoqun Huang ◽  
Xiaoyun Yang ◽  
Gayan Bamunuarachchi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Noncoding Rna ◽  
Mammalian Target Of Rapamycin ◽  
Lung Fibroblasts ◽  
Mrna Levels ◽  
Fibroblast Proliferation ◽  
Protein Levels ◽  
Key Characteristics ◽  
Ribosomal S6 Kinase

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and usually lethal lung disease and it has been widely accepted that fibroblast proliferation is one of the key characteristics of IPF. Long noncoding RNAs (lncRNAs) play vital roles in the pathogenesis of many diseases. In this study, we investigated the role of lncRNA FENDRR on fibroblast proliferation. Human lung fibroblasts stably overexpressing FENDRR showed a reduced cell proliferation compared to those expressing the control vector. On the other hand, FENDRR silencing increased fibroblast proliferation. FENDRR bound serine-arginine rich splicing factor 9 (SRSF9) and inhibited the phosphorylation of p70 ribosomal S6 kinase 1 (PS6K), a downstream protein of the mammalian target of rapamycin (mTOR) signaling. Silencing SRSF9 reduced fibroblast proliferation. FENDRR reduced β-catenin protein, but not mRNA levels. The reduction of β-catenin protein levels in lung fibroblasts by gene silencing or chemical inhibitor decreased fibroblast proliferation. Adenovirus-mediated FENDRR transfer to the lungs of mice reduced asbestos-induced fibrotic lesions and collagen deposition. RNA sequencing of lung tissues identified 7 cell proliferation-related genes that were up-regulated by asbestos but reversed by FENDRR. In conclusion, FENDRR inhibits fibroblast proliferation and functions as an anti-fibrotic lncRNA.

scholarly journals The Role of the FOXO1/β2-AR/p-NF-κB p65 Pathway in the Development of Endometrial Stromal Cells in Pregnant Mice under Restraint Stress

2021 ◽  
Vol 22 (3) ◽  
pp. 1478
Author(s):  
Jiayin Lu ◽  
Yaoxing Chen ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong
Keyword(s):  
Oxidative Stress ◽  
Stromal Cells ◽  
Restraint Stress ◽  
Target Genes ◽  
Mrna Levels ◽  
Endometrial Stromal Cells ◽  
Protein Levels ◽  
Pregnant Mice

Restraint stress causes various maternal diseases during pregnancy. β2-Adrenergic receptor (β2-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β2-AR pathway in pregnant mice, has been unclear. The aim of this research was to investigate the β2-AR pathway of restraint stress and its impact on the oxidative stress of the maternal uterus. In the study, maternal mice were treated with restraint stress by being restrained in a transparent and ventilated device before sacrifice on Pregnancy Day 5 (P5), Pregnancy Day 10 (P10), Pregnancy Day 15 (P15), and Pregnancy Day 20 (P20) as well as on Non-Pregnancy Day 5 (NP5). Restraint stress augmented blood corticosterone (CORT), norepinephrine (NE), and blood glucose levels, while oestradiol (E2) levels decreased. Moreover, restraint stress increased the mRNA levels of the FOXO family, β2-AR, and even the protein levels of FOXO1 and β2-AR in the uterus and ovaries. Furthermore, restraint stress increased uterine oxidative stress level. In vitro, the protein levels of FOXO1 were also obviously increased when β2-AR was activated in endometrial stromal cells (ESCs). In addition, phosphorylated-nuclear factor kappa-B p65 (p-NF-κB p65) and its target genes decreased significantly when FOXO1 was inhibited. Overall, it can be said that the β2-AR/FOXO1/p-NF-κB p65 pathway was activated when pregnant mice were under restraint stress. This study provides a scientific basis for the origin of psychological stress in pregnant women.

IL-4 and IL-13 upregulate arginase I expression by cAMP and JAK/STAT6 pathways in vascular smooth muscle cells

2000 ◽  
Vol 279 (1) ◽  
pp. C248-C256 ◽  
Author(s):  
Liu Hua Wei ◽  
Aaron T. Jacobs ◽  
Sidney M. Morris ◽  
Louis J. Ignarro
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Growth ◽  
Muscle Cells ◽  
Protein Levels ◽  
Ifn Γ ◽  
Arginase Ii ◽  
Arginase I

The objectives of this study were to determine whether rat aortic smooth muscle cells (RASMC) express arginase and to elucidate the possible mechanisms involved in the regulation of arginase expression. The results show that RASMC contain basal arginase I (AI) activity, which is significantly enhanced by stimulating the cells with either interleukin (IL)-4 or IL-13, but arginase II (AII) expression was not detected under any condition studied here. We further investigated the signal transduction pathways responsible for AI induction. AI mRNA and protein levels were enhanced by addition of forskolin (1 μM) and inhibited by H-89 (30 μM), suggesting positive regulation of AI by a protein kinase A pathway. Genistein (10 μg/ml) and sodium orthovanadate (Na3VO4; 10 μM) were used to investigate the role of tyrosine phosphorylation in the control of AI expression. Genistein inhibited, whereas Na3VO4enhanced the induction of AI by IL-4 or IL-13. Along with immunoprecipitation and immunoblot analyses, these data implicate the JAK/STAT6 pathway in AI regulation. Dexamethasone (Dex) and interferon (IFN)-γ were investigated for their effects on AI induction. Dex (1 μM) and IFN-γ (100 U/ml) alone had no effect on basal AI expression in RASMC, but both reduced AI induction by IL-4 and IL-13. In combination, Dex and IFN-γ abolished AI induction by IL-4 and IL-13. Finally, both IL-4 and IL-13 significantly increased RASMC DNA synthesis as monitored by [3H]thymidine incorporation, demonstrating that upregulation of AI is correlated with an increase in cell proliferation. Blockade of AI induction by IFN-γ, H-89, or genistein also blocked the increase in cell proliferation. These observations are consistent with the possibility that upregulation of AI might play an important role in the pathophysiology of vascular disorders characterized by excessive smooth muscle growth.

Role of mTOR1 and mTOR2 complexes in MEG-01 cell physiology

2015 ◽  
Vol 114 (11) ◽  
pp. 969-981 ◽  
Author(s):  
Esther López ◽  
Alejandro Berna-Erro ◽  
Javier J. López ◽  
María P. Granados ◽  
Nuria Bermejo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Cell Physiology ◽  
Cell Stimulation ◽  
Intracellular Location ◽  
Macromolecular Complexes

SummaryThe function of the mammalian target of rapamycin (mTOR) is upregulated in response to cell stimulation with growing and differentiating factors. Active mTOR controls cell proliferation, differentiation and death. Since mTOR associates with different proteins to form two functional macromolecular complexes, we aimed to investigate the role of the mTORI and mTOR2 complexes in MEG-01 cell physiology in response to thrombopoietin (TPO). By using mTOR antagonists and overexpressing FKBP38, we have explored the role of both mTOR complexes in proliferation, apoptosis, maturation-like mechanisms, endoplasmic reticulum-stress and the intracellular location of both active mTOR complexes during MEG-01 cell stimulation with TPO. The results demonstrate that mTOR1 and mTOR2 complexes play different roles in the physiology of MEG-01 cells and in the maturation-like mechanisms; hence, these findings might help to understand the mechanism underlying generation of platelets.

scholarly journals BAG3 contributes to HGF-mediated cell proliferation, migration, and invasion via the Egr1 pathway in gastric cancer

2018 ◽  
Vol 105 (1) ◽  
pp. 63-75
Author(s):  
Jae Chang Lee ◽  
Sung Ae Koh ◽  
Kyung Hee Lee ◽  
Jae-Ryong Kim
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Human Gastric Cancer ◽  
Protein Levels ◽  
Dependent Pathway

Introduction: Bcl2-associated athanogene 3 (BAG3) is elevated in several types of cancers. However, the role of BAG3 in progression of gastric cancer is unknown. Therefore, the present study aims to find out the role of BAG3 in hepatocyte growth factor (HGF)–mediated tumor progression and the molecular mechanisms by which HGF regulates BAG3 expression. Methods: BAG3 mRNA and protein were measured using reverse transcription polymerase chain reaction and Western blot in the 2 human gastric cancer cell lines, NUGC3 and MKN28, treated with or without HGF. The effects of BAG3 knockdown on cell proliferation, cell invasion, and apoptosis were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the in vitro 2-chamber invasion assay, and flow cytometry in BAG3 short hairpin RNA (shRNA)–transfected cells and control cells. The signaling pathways involved in BAG3 that are regulated by HGF were analyzed. The chromatin immunoprecipitation assay was used to determine binding of Egr1 to the BAG3 promoter. Results: BAG3 mRNA and protein levels were increased following treatment with HGF. HGF-mediated BAG3 upregulation increased cell proliferation and cell invasion; however, it decreased apoptosis. HGF-mediated BAG3 upregulation is regulated by an ERK and Egr1-dependent pathway. BAG3 may have an important role in HGF-mediated cell proliferation and metastasis in gastric cancer through an ERK and Egr1-dependent pathway. Conclusion: This pathway may provide novel therapeutic targets and provide information for further identification of other targets of therapeutic significance in gastric cancer.

Abstract P207: Role of (Pro)Renin Receptor in the Pathogenesis of Colon Cancer

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Akira Nishiyama ◽  
Juan Wang ◽  
Shinichi Yachida ◽  
Genevieve Nguyen ◽  
Takuo Hirose ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Signaling Pathway ◽  
Western Blotting ◽  
Cell Number ◽  
Ductal Adenocarcinoma ◽  
Mrna Levels ◽  
Protein Levels ◽  
Colon Cancer Cell Lines ◽  
Cancer Tissues

(Pro)renin receptor ((P)RR) is a component of the Wnt receptor complex (Science, 2010). We have recently demonstrated that (P)RR plays an important role in the tumorigenesis of pancreatic ductal adenocarcinoma via the activation of Wnt/β-catenin signaling pathway (Shibayama et al. Sci Rep. 2015). Since the patients with colon cancer often show aberrantly activated Wnt/β-catenin-dependent signaling pathway by the mutations of its components, we investigated the possible role of (P)RR and Wnt/β-catenin signaling pathway in carcinogenesis of colon cancer. Real-time PCR was used for measuring mRNA levels of (P)RR. Protein levels of (P)RR was determined by Western blotting and immunohistochemistry. Activated β-catenin levels were determined by Western blotting. Cell proliferative ability was evaluated by counting the cell number in cultured colon cancer cell lines, HCT116 and DLD-1 cells. As compared to normal colon tissues (n=6), mRNA and protein levels of (P)RR were increased by 2.6- and 2.2-fold, respectively, in colon cancer tissues (n=9), which were associated with increased activated β-catenin levels (by 2.8-fold, P<0.05). However, plasma soluble (P)RR levels were not changed in patients with colon cancer (n=9). (P)RR and activated β-catenin levels were also increased in HCT116 (by 2.2- and 2.7-fold, n=5, respectively) and DLD-1 cells (by 1.9- and 2.8-fold, n=5, respectively). In these cells, inhibiting (P)RR with an siRNA attenuated the activity of β-catenin and reduced the proliferative abilities (n=5, P<0.05, respectively). These data suggest that (P)RR contributes to the tumorigenesis of colon cancer through the activation of Wnt/β-catenin signaling pathway.

S100A4 promotes the progression of lipopolysaccharide-induced acute epididymitis in mice†

2020 ◽  
Vol 102 (6) ◽  
pp. 1213-1224 ◽  
Author(s):  
Yingjie Wu ◽  
Haoran Li ◽  
Yinghe Qin
Keyword(s):  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Mrna Levels ◽  
Ki 67 ◽  
Tnf Α ◽  
Proliferation And Apoptosis ◽  
Sperm Membrane ◽  
Marked Cell ◽  
Acute Epididymitis

Abstract S100A4 has been suggested to be a critical regulator of tumor metastasis and is implicated in the progression of inflammation. The aim of this study is to investigate the expression and possible role of S100A4 in epididymitis. Using a mouse model of epididymitis induced by the injection of lipopolysaccharide (LPS) in the deferent duct, we found that LPS administration induced an upregulation of S100a4 transcription (P &lt; 0.05) and a recruitment of S100A4 positive cells in the epididymal interstitium of wild type (WT) mice. Co-immunofluorescence showed that S100A4 was mainly expressed by granulocytes, CD4 lymphocytes, and macrophages. Deficiency of S100A4 reduced epididymal pathological reaction and the mRNA levels of the pro-inflammatory cytokines IL-1β and TNF-α (P &lt; 0.01), suggesting that S100A4 promotes the progression of epididymitis. Furthermore, S100A4 deficiency alleviated the decline of sperm motility and rectified the abnormal expression of sperm membrane protein AMAD3, which suggested that in the progression of epididymitis, S100A4 aggravates the damage to sperm vitality. In addition, both Ki-67 marked cell proliferation and transferase-mediated dUTP-biotin nick end labeling detected cell apoptosis were reduced in S100a4−/− mice compared with WT mice after LPS treatment, indicating that S100A4 promotes both cell proliferation and cell apoptosis in epididymitis. Overall, these results demonstrate that S100A4 promotes the progression of LPS-induced epididymitis and facilitates a decline in sperm vitality, and its function may be related to the process of cell proliferation and apoptosis during inflammation.

scholarly journals MicroRNA-126-3p Inhibits Angiogenic Function of Human Lung Microvascular Endothelial Cells via LAT1 (L-Type Amino Acid Transporter 1)-Mediated mTOR (Mammalian Target of Rapamycin) Signaling

2020 ◽  
Vol 40 (5) ◽  
pp. 1195-1206 ◽  
Author(s):  
Danting Cao ◽  
Andrew M. Mikosz ◽  
Alexandra J. Ringsby ◽  
Kelsey C. Anderson ◽  
Erica L. Beatman ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Amino Acid ◽  
Cell Apoptosis ◽  
Human Lung ◽  
Mammalian Target Of Rapamycin ◽  
Tube Formation ◽  
Microvascular Endothelial Cells ◽  
Microvascular Endothelial

Objective: MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. Conclusions: miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.

scholarly journals Lentivirus-Mediated siRNA Targeting ER-αInhibits Tumorigenesis and Induces Apoptosis in Hepatocarcinoma Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Ping Jiang ◽  
Jun Cao ◽  
Wen-Hui Bai
Keyword(s):  
Cell Proliferation ◽  
Cell Cycle Progression ◽  
Dependent Manner ◽  
Gene Therapy Approach ◽  
Protein Levels ◽  
Human Liver Cancer ◽  
Hepatocarcinoma Cells ◽  
Interfering Rna ◽  
Hcc Cells

Background and Objectives. Estrogen receptor-α(ER-α) plays important roles in hepatocarcinogenesis. Recent studies have shown that ER-αcould lead to cell cycle progression or inhibition of apoptosis. To better understand the role of ER-α, RNA interference (RNAi) was used to inhibit ER-αexpression in the human hepatocellular carcinoma (HCC) cells.Methods. Lentivirus-mediated ER-αsmall interfering RNA (siRNA) was transfected into HCC cells Hep3B. ER-αexpression was monitored by real-time polymerase chain reaction (PCR) and western blot. Cell proliferation, apoptosis, and invasion were examined by methyl thiazol tetrazolium (MTT), flow cytometry (FCM), and invasion assay, respectively.Results. ER-αsiRNA efficiently downregulated the expression of ER-αin Hep3B cells at both mRNA and protein levels in a time-dependent manner. ER-αsiRNA also inhibited cell proliferation and reduced cell invasion (compared with other groups,P<0.05, resp.). Furthermore, knockdown of ER-αslowed down the cell population at S phase and increased the rate of apoptosis (P<0.05, resp.).Conclusion. ER-αknockdown suppressed the growth of HCC cells. Thus, ER-αmay play a very important role in carcinogenesis of HCC and its knockdown may offer a new potential gene therapy approach for human liver cancer in the future.

scholarly journals MicroRNA-96 inhibits FoxO3a function in IPF fibroblasts on type I collagen matrix

2014 ◽  
Vol 307 (8) ◽  
pp. L632-L642 ◽  
Author(s):  
Richard Seonghun Nho ◽  
Jintaek Im ◽  
Yen-Yi Ho ◽  
Polla Hergert
Keyword(s):  
Type I Collagen ◽  
Collagen Matrix ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels ◽  
Dose Dependent Fashion ◽  
Mrna And Protein Expression

Idiopathic pulmonary fibrosis (IPF) is a lethal and progressive lung disease characterized by persistent (myo)fibroblasts and the relentless accumulation of collagen matrix. Unlike normal lung fibroblasts, IPF lung fibroblasts have suppressed forkhead box O3a (FoxO3a) activity, which allows them to expand in this diseased environment. microRNA-96 (miR-96) has recently been found to directly bind to the 3′-untranslated region of FoxO3a mRNA, which subsequently inhibits its function. We examined whether aberrantly low FoxO3a expression is in part due to increased miR-96 levels in IPF fibroblasts on polymerized collagen, thereby causing IPF fibroblasts to maintain their pathological properties. miR-96 expression was upregulated in IPF fibroblasts compared with control fibroblasts when cultured on collagen. In contrast, FoxO3a mRNA levels were reduced in most IPF fibroblasts. However, when miR-96 function was inhibited, FoxO3a mRNA and protein expression were increased, suppressing IPF fibroblast proliferation and promoting their cell death in a dose-dependent fashion. Likewise, FoxO3a and its target proteins p21, p27, and Bim expression was also increased in the presence of a miR-96 inhibitor in IPF fibroblasts. However, when control fibroblasts were treated with miR-96 mimic, FoxO3a, p27, p21, and Bim mRNA and protein levels were decreased. In situ hybridization analysis further revealed the presence of enhanced miR-96 expression in cells within the fibroblastic foci of IPF lung tissue. Our results suggest that when IPF fibroblasts interact with collagen-rich matrix, pathologically altered miR-96 expression inhibits FoxO3a function, causing IPF fibroblasts to maintain their pathological phenotype, which may contribute to the progression of IPF.

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