Quercetin Induces Apoptosis in Glioblastoma Cells by Suppressing Axl/IL-6/STAT3 Signaling Pathway

2021 ◽  
Vol 49 (03) ◽  
pp. 767-784
Author(s):  
Hyo In Kim ◽  
Sol Ji Lee ◽  
Yu-Jeong Choi ◽  
Min Jeong Kim ◽  
Tai Young Kim ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Treatment Options ◽  
Primary Brain Tumor ◽  
Cancer Microenvironment ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Mitogen Activated Protein ◽  
Apoptotic Effect ◽  
Quercetin Treatment

Gliomas are the mostly observed form of primary brain tumor, and glioblastoma multiforme (GBM) shows the highest incidence. The survival rate of GBM is fairly poor; thus, discovery of effective treatment options is required. Among several suggested targets for therapy, the Axl/IL-6/STAT3 signaling pathway has gained recent interest because of its important role within cancer microenvironment. Quercetin, a plant flavonoid, is well known for its anticancer action. However, the effect of quercetin on Axl has never been reported. Quercetin treatment significantly reduced cell viability in two GBM cell lines of U87MG and U373MG while keeping 85% of normal astrocytes alive. Further western blot assays suggested that quercetin induces apoptosis but does not affect Akt or mitogen-activated protein kinases, factors related to cell proliferation. Quercetin also decreased IL-6 release and phosphorylation of STAT3 in GBM cells. In addition, gene expression, protein expression, and half-life of synthesized Axl protein were all suppressed by quercetin. By applying shRNA for knockdown of Axl, we could confirm that the role of Axl was crucial in the apoptotic effect of quercetin on GBM cells. In conclusion, we suggest quercetin as a potential anticancer agent, which may improve cancer microenvironment of GBM via the Axl/IL-6/STAT3 pathway.

scholarly journals Knockout of NOS2 Promotes Adipogenic Differentiation of Rat MSCs by Enhancing Activation of JAK/STAT3 Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Aiping Qin ◽  
Sheng Chen ◽  
Ping Wang ◽  
Xiaotao Huang ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Adipogenic Differentiation ◽  
Marker Genes ◽  
Sprague Dawley ◽  
Differentiation Potential ◽  
Ppar Γ ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Mesenchymal stromal cells (MSCs) are a heterogeneous population of cells that possess multilineage differentiation potential and extensive immunomodulatory properties. In mice and rats, MSCs produce nitric oxide (NO), as immunomodulatory effector molecule that exerts an antiproliferative effect on T cells, while the role of NO in differentiation was less clear. Here, we investigated the role of NO synthase 2 (NOS2) on adipogenic and osteogenic differentiation of rat MSCs. MSCs isolated from NOS2-null (NOS2–/–) and wild type (WT) Sprague–Dawley (SD) rats exhibited homogenous fibroblast-like morphology and characteristic phenotypes. However, after induction, adipogenic differentiation was found significantly promoted in NOS2–/– MSCs compared to WT MSCs, but not in osteogenic differentiation. Accordingly, qRT-PCR revealed that the adipogenesis-related genes PPAR-γ, C/EBP-α, LPL and FABP4 were markedly upregulated in NOS2–/– MSCs, but not for osteogenic transcription factors or marker genes. Further investigations revealed that the significant enhancement of adipogenic differentiation in NOS2–/– MSCs was due to overactivation of the STAT3 signaling pathway. Both AG490 and S3I-201, small molecule inhibitors that selectively inhibit STAT3 activation, reversed this adipogenic effect. Furthermore, after high-fat diet (HFD) feeding, knockout of NOS2 in rat MSCs resulted in significant obesity. In summary, NOS2 is involved in the regulation of rat MSC adipogenic differentiation via the STAT3 signaling pathway.

The role of JAK-STAT3 signaling pathway during fetal lung development

2008 ◽  
Vol 84 ◽  
pp. S79-S80 ◽  
Author(s):  
Cristina Nogueira-Silva ◽  
Susana Nunes ◽  
Rute S. Moura ◽  
Jorge Correia-Pinto
Keyword(s):  
Signaling Pathway ◽  
Lung Development ◽  
Fetal Lung ◽  
Stat3 Signaling ◽  
Fetal Lung Development ◽  
Stat3 Signaling Pathway

scholarly journals IL-37 Exerts Anti-Inflammatory Effects in Fetal Membranes of Spontaneous Preterm Birth via the NF-κB and IL-6/STAT3 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Lulu Wang ◽  
Zheng Liu ◽  
Dongni Huang ◽  
Yuxin Ran ◽  
Hanwen Zhang ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Signaling Pathway ◽  
Biological Effects ◽  
Clinical Samples ◽  
Fetal Membranes ◽  
Spontaneous Preterm Birth ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Anti Inflammatory

Spontaneous preterm birth (sPTB), defined as delivery before 37 weeks of gestation, is thought to be a multifactorial syndrome. However, the inflammatory imbalance at the maternal-fetal interface promotes excessive secretion of inflammatory factors and induces apoptosis and degradation of the extracellular matrix (ECM), which can subsequently lead to preterm birth. As an anti-inflammatory molecule in the IL-1 family, interleukin-37 (IL-37) mainly plays an inhibiting role in a variety of inflammatory diseases. However, as a typical inflammatory disease, no previous studies have been carried out to explore the role of IL-37 in sPTB. In this study, a series of molecular biological experiments were performed in clinical samples and human amniotic epithelial cell line (Wistar Institute Susan Hayflick (WISH)) to investigate the deficiency role of IL-37 and the potential mechanism. Firstly, the results indicated that the expression of IL-37 in human peripheral plasma and fetal membranes was significantly decreased in the sPTB group. Afterward, it is proved that IL-37 could significantly suppress the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in WISH cells. Simultaneously, once silence IL-37, LPS-induced apoptosis and activity of matrix metalloproteinases (MMPs) 2 and 9 were significantly increased. In addition, the western blot data showed that IL-37 performed its biological effects by inhibiting the NF-κB and IL-6/STAT3 pathway. In conclusion, our results suggest that IL-37 limits excessive inflammation and subsequently inhibits ECM remodeling and apoptosis through the NF-κB and IL-6/STAT3 signaling pathway in the fetal membranes.

scholarly journals MFG-E8 attenuates neuro-inflammation in subarachnoid hemorrhage through driving microglial M2 polarization via modulating Integrin β3/SOCS3/STAT3 signaling pathway

2020 ◽  
Author(s):  
Yongyue Gao ◽  
Zong Zhuang ◽  
Yue Lu ◽  
Lingyun Wu ◽  
Guangjie Liu ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Signaling Pathway ◽  
Microglial Polarization ◽  
Integrin Β3 ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Neuro Inflammation ◽  
Anti Inflammation ◽  
M2 Phenotype

Abstract Background Increasing evidence suggests microglial polarization plays an important role in the pathological processes of neuro-inflammation following subarachnoid hemorrhage (SAH). Previous studies indicated that milk fat globule-EGF factor-8 (MFG-E8) has the potential in anti-apoptosis and anti-inflammation in cerebral ischemia. However, the effects of MFG-E8 on microglial polarization have not been evaluated after SAH. Therefore, the aim of this study was to explore the role of MFG-E8 on anti-inflammation, and its potential mechanism on microglial polarization following SAH. Methods We established the SAH model via prechiasmatic cistern Blood injection in mice. Double-immunofluorescence staining, Western blotting and quantitative real-time polymerase chain reaction (q-PCR) were performed to investigate the expression and cellular distribution of MFG-E8. Two different dosages (1 μg and 5 μg) of recombinant human MFG-E8 (rhMFG-E8) were injected intracerebroventricular (i.c.v.) at 1 h after SAH. Brain water content, neurological scores, beam-walking score, Fluoro-Jade C (FJC) and terminal deoxynucleotidyl transferase dUTP nick endlabeling staining (TUNEL) were measured at 24 h. Intervention of MFG-E8, integrin β3 and phosphorylation of STAT3 were achieved by specific siRNAs (500 pmol/5 µl) and STAT3 inhibitor Stattic (5 µM). The potential signal pathway and microglial polarization were measured by immunofluorescence labeling and Western blotting. Results SAH induction increased the levels of inflammation mediators, the proportion of M1 and caused neuronal apoptosis in mice at 24 h. Treatment with rhMFG-E8 (5 µg) remarkably decreased brain edema, improved neurological functions, reduced the levels of pro-inflammation factors, and promoted microglia shifted to M2 phenotype. However, knockdown MFG-E8 and integrin β3 via siRNA abolished the effects of MFG-E8 on anti-inflammation and M2 phenotype polarization. STAT3 inhibitor Stattic further clarified the role of rhMFG-E8 on microglial polarization through regulating the protein levels of integrin β3/SOCS3/STAT3 pathway. Conclusions rhMFG-E8 inhibits neuron-inflammation through transformation microglial phenotype towards M2 after SAH, which may be mediated by modulation of the integrin β3/SOCS3/STAT3 signaling pathway, and highlighting rhMFG-E8 as a potentially therapeutic target for the treatment of SAH patients.

scholarly journals LINC00893 Inhibits The Progression of Prostate Cancer Through miR-3173-5p/SOCS3/JAK2/STAT3 Pathway

2021 ◽  
Author(s):  
Chuigong Yu ◽  
Yu Fan ◽  
Yu Zhang ◽  
Lupeng Liu ◽  
Gang Guo
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Janus Kinase ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Stat3 Pathway ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background: Prostate cancer (PCa) is one of the most common malignant tumors in the male urinary system. In recent years, the morbidity and mortality of PCa have been increasing due to the limited effects of existing treatment strategies. Long non-coding RNA (lncRNA) LINC00893 inhibits the proliferation and metastasis of papillary thyroid cancer (PTC) cells, but its role in PCa has not been reported. Our study aims to clarify the role and underlying mechanism of LINC00893 in regulating the progression of PCa.Methods: We analyzed LINC00893 expression through TCGA database. We also collected 66 paires of PCa tissues and matched para-cancerous tissues as well as cell lines and assessed LINC00893 expression. Subsequently, we conducted gain-of-function assays to confirm the role of LINC00893 in PCa. CCK-8, EdU, colony information and transwell assays were implemented to detect cell proliferation, colony formation and metastasis abilities, respectively. RT-qPCR and western blot assays were used to quantify the expression of mRNA and protein. Dual-luciferase reporter, RNA-binding protein immunoprecipitation (RIP) and RNA pull down assays were conducted to evaluate the interaction of molecules. Spearman correlation coefficient analysis was conducted to detect the correlation between molecules.Results: We found that the LINC00893 expression in PCa tissues and cell lines was upregulated compared with matched controls, and patients with low expression of LINC00893 suffered a low overall survival rate. Overexpression of LINC00893 hindered the proliferation, epithelial-mesenchymal transition (EMT) as well as metastasis of PCa cells in vitro and in vivo. In terms of mechanism, suppressor of cytokine signaling 3 (SOCS3)/Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway occupied a central position in the regulation of PCa progression by LINC00893. LINC00893 weakened the inhibition role of miR-3173-5p on SOCS3 expression through functioning as a miR-3173-5p sponge, which inhibited the JAK2/STAT3 signaling pathway. Conclusions: LINC00893 suppresses the progression of prostate cancer through miR-3173-5p/SOCS3/JAK2/STAT3 pathway. our data uncovers a novel mechanism by which LINC00893 hinders the progression of PCa, which enriches the molecular network of LINC00893 regulating the PCa progression and laies a theoretical foundation for PCa targeted therapy.

scholarly journals RNA-seq and In Vitro Experiments Reveal the Protective Effect of Curcumin against 5-Fluorouracil-Induced Intestinal Mucositis via IL-6/STAT3 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Xuan-ying Wang ◽  
Bo Zhang ◽  
Yi Lu ◽  
Lu Xu ◽  
Yi-jie Wang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Intestinal Epithelial Cells ◽  
Sequencing Analysis ◽  
Intestinal Epithelial ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Intestinal Mucositis

Although first-line chemotherapy drugs, including 5-fluorouracil (5-FU), remain one of the major choice for cancer treatment, the clinical use is also accompanied with dose-depending toxicities, such as intestinal mucositis (IM), in cancer patients undergoing treatment. IM-induced gastrointestinal adverse reactions become frequent reason to postpone chemotherapy and have negative impacts on therapeutic outcomes and prognosis. Various studies have evidenced the anticancer role of curcumin in many cancers; except for this effect, studies also indicated a protective role of curcumin in intestinal diseases. Therefore, in this study, we investigated the effect of curcumin on inflammation, intestinal epithelial cell damage in an IM model. 5-FU was used to induce the model of IM in intestinal epithelial cells, and curcumin at different concentrations was administrated. The results showed that curcumin efficiently attenuated 5-FU-induced damage to IEC-6 cells, inhibited the levels of inflammatory cytokines, attenuated the 5-FU-induced inhibition on cell viability, and displayed antiapoptosis effect on IEC-6 cells. Further RNA-sequencing analysis and experiment validation found that curcumin displays its protective effect against 5-FU-induced IM in intestinal epithelial cells by the inhibition of IL-6/STAT3 signaling pathway. Taken together, these findings suggested that curcumin may be provided as a therapeutic agent in prevention and treatment of chemotherapy-induced IM.

Lipopolysaccharide induces epithelial–mesenchymal transition of alveolar epithelial cells cocultured with macrophages possibly via the JAK2/STAT3 signaling pathway

2019 ◽  
Vol 39 (2) ◽  
pp. 224-234 ◽  
Author(s):  
Y Qin ◽  
P Zhao ◽  
Y Chen ◽  
X Liu ◽  
H Dong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Markers ◽  
Epithelial Mesenchymal Transition ◽  
A549 Cells ◽  
Alveolar Epithelial Cells ◽  
Mesenchymal Transition ◽  
Alveolar Epithelial ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Epithelial–mesenchymal transition (EMT) plays a key role in the process of pulmonary fibrosis (PF). Increasing evidences have shown that exaggerated EMT in recurrent pulmonary injury mediates the early pathogenesis of PF. This study aimed to evaluate EMT of human alveolar epithelial cells (A549) when cocultured with human macrophages Tohoku hospital pediatrics-1 (THP-1) induced by lipopolysaccharide (LPS) and investigate the role of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Firstly, we detected the inflammatory and EMT biomarkers in A549 cells monoculture and A549/THP-1 cells coculture in the presence or absence of LPS. Then, the activation of JAK2/STAT3 signaling pathway was determined in coculture. Interestingly, inflammatory markers, such as interleukin (IL)-6, matrix metalloproteinase (MMP)-9, transforming growth factor (TGF)- β, and collagen type 1 (COL-1), were enhanced in LPS treated coculture. Besides, the expression of E-cadherin decreased but α-smooth muscle actin expression increased, indicating the presence of EMT in A549 cells when cocultured with THP-1 macrophages. However, these phenotypes could not be observed in LPS-treated A549 cells monoculture. Meanwhile, JAK2/STAT3 signaling pathway was activated, and the STAT3 DNA-binding and inflammatory markers were inhibited by Stattic. Together, these findings demonstrate the key role of JAK2/STAT3 signaling pathway in LPS promoted EMT of A549 in the presence of THP-1 macrophages as an in vitro PF model.

Sign in / Sign up

Export Citation Format

Share Document