scholarly journals A Comprehensive Assessment of Apigenin as an Antiproliferative, Proapoptotic, Antiangiogenic and Immunomodulatory Phytocompound

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 858 ◽  
Author(s):  
Alexandra Ghițu ◽  
Anja Schwiebs ◽  
Heinfried H. Radeke ◽  
Stefana Avram ◽  
Istvan Zupko ◽  
...  
Keyword(s):  
Comprehensive Evaluation ◽  
Annexin V ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
Cell Growth And Migration ◽  
Atp Production ◽  
Lactate Dehydrogenase Release ◽  
High Concentrations ◽  
And Migration ◽  
Lps Activation

Apigenin (4′,5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 μM and 60 μM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.

scholarly journals Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 787 ◽  
Author(s):  
Rosalba D’Alessandro ◽  
Maria Grazia Refolo ◽  
Palma Aurelia Iacovazzi ◽  
Pasqua Letizia Pesole ◽  
Caterina Messa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Growth Factor Receptor ◽  
Annexin V ◽  
Therapeutic Effects ◽  
Experimental Conditions ◽  
Cell Growth And Migration ◽  
Low Concentrations ◽  
And Migration ◽  
Endothelial Growth Factor

Several new multikinase inhibitors have recently been introduced into clinical practice for hepatocellular carcinoma (HCC) therapy. Small increases in survival were reported as well as considerable toxicity. There is thus a need for effective therapies with lower toxicities. We examined whether a combination of sorafenib and regorafenib might also be effective at very low concentrations, with resulting potential for lessened clinical toxicity. MTT test, clonogenic assay, Ki67 staining and cell cycle analysis were assessed for cell proliferation and Annexin V and western blotting analysis relative to the expression of cleaved Caspase-3 and BID for cell apoptosis. In these experimental conditions cell growth and migration were potently inhibited and apoptosis induced even in HCC cells producing high alpha fetoprotein (AFP) levels (clinically worse prognosis). The combination also inhibited levels of the two HCC biomarkers, AFP and des gamma carboxy prothrombin (DCP). Additional inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR) or Insulin-like Growth Factor 1 Receptor (IGF1R) enhanced effects on AFP and DCP levels, cell growth inhibition and MAPK and PI3K/Akt signaling inhibition due to sorafenib/regorafenib combination. These combinations have the potential for decreased toxicity while simultaneously enhancing therapeutic effects. This potential decrease in toxicity is being explored in ongoing studies.

scholarly journals Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Onur Cizmecioglu ◽  
Jing Ni ◽  
Shaozhen Xie ◽  
Jean J Zhao ◽  
Thomas M Roberts
Keyword(s):  
Plasma Membrane ◽  
Physiological Role ◽  
Dependent Manner ◽  
Membrane Raft ◽  
Cell Growth And Migration ◽  
Gpcr Signaling ◽  
Pten Loss ◽  
And Migration ◽  
Phosphoinositide 3 Kinase ◽  
Genetic Targeting

We aimed to understand how spatial compartmentalization in the plasma membrane might contribute to the functions of the ubiquitous class IA phosphoinositide 3-kinase (PI3K) isoforms, p110α and p110β. We found that p110β localizes to membrane rafts in a Rac1-dependent manner. This localization potentiates Akt activation by G-protein-coupled receptors (GPCRs). Thus genetic targeting of a Rac1 binding-deficient allele of p110β to rafts alleviated the requirement for p110β-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110α, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110α allowed its EGFR-mediated activation by GPCRs. Notably, p110β dependent, PTEN null tumor cells critically rely upon raft-associated PI3K activity. Collectively, our findings provide a mechanistic account of how membrane raft localization regulates differential activation of distinct PI3K isoforms and offer insight into why PTEN-deficient cancers depend on p110β.

scholarly journals FGFR Signaling Coordinates the Balance Between Glycolysis and Fatty Acid β-Oxidation in Lymphatic Endothelial Cells

2020 ◽  
Author(s):  
Hongyuan Song ◽  
Jie Zhu ◽  
Longhou Fang ◽  
Pengchun Yu
Keyword(s):  
Endothelial Cells ◽  
Fatty Acid ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Lymphatic Endothelial Cells ◽  
Energy Deficiency ◽  
Atp Production ◽  
Atp Generation ◽  
And Migration ◽  
A Minor

AbstractThe balance between glycolysis and oxidative phosphorylation is believed to be critical for maintaining cellular bioenergetics, yet the regulation of such balance in lymphatic endothelial cells (LECs) remains unclear. Here we found that chemical inhibition of fibroblast growth factor receptor (FGFR) activity or knockdown of FGFR1, which has been shown to suppress glycolysis and consequently ATP production, induces substantial upregulation of fatty acid β-oxidation (FAO), but not glucose oxidation or glutamine oxidation in LECs. Mechanistically, blockade of FGFR-AKT signaling promotes the expression of CPT1A, a rate-limiting enzyme of FAO, in a PPARα-dependent manner. Metabolic analysis further showed that CPT1A depletion impairs ATP generation in FGFR1-deficient rather than wild-type LECs. This result suggests that FAO, which makes a minor contribution to cellular energy under normal conditions, can compensate for energy deficiency caused by FGFR inhibition. Consequently, CPT1A silencing potentiates the effect of FGFR1 knockdown on impeding LEC proliferation and migration. Collectively, our study identified an FGFR-regulated metabolic balance that is important for LEC growth.

TSPAN8 promotes colorectal cancer cell growth and migration in LSD1-dependent manner

Life Sciences ◽  
2020 ◽  
Vol 241 ◽  
pp. 117114 ◽  
Author(s):  
Hong-Sheng Zhang ◽  
Hui-Yun Liu ◽  
Zhen Zhou ◽  
Hong-Liang Sun ◽  
Min-Yao Liu
Keyword(s):  
Colorectal Cancer ◽  
Cell Growth ◽  
Cancer Cell ◽  
Colorectal Cancer Cell ◽  
Dependent Manner ◽  
Cancer Cell Growth ◽  
Cell Growth And Migration ◽  
And Migration

scholarly journals Fibronectin within Sodium Alginate Microcapsules Improved Osteogenic Differentiation of BMMSCs in Dose Dependent Manner by Targeting SP7, OCN, CDK1, ZBTB16, and Twist1 Expression

2021 ◽  
Author(s):  
Karim Shamsasenjan ◽  
Younes Beygi Khosrowshahi ◽  
Mahsa Mahmoodi ◽  
Parvin Akbarzadehlaleh ◽  
Nesrin Gareayaghi ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Sodium Alginate ◽  
Annexin V ◽  
Bhlh Transcription Factor ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Limited Information ◽  
Peroxisome Proliferator Activated Receptor ◽  
Gel Injection ◽  
And Migration

Introduction: Insoluble fibronectin as an extracellular matrix (ECM) protein has the potential to promote proliferation, differentiation, and migration of mesenchymal stem cells (MSCs). However, there is limited information about the effects of fibronectin various concentrations on bone marrow-derived MSCs (BMMSCs) function and differentiation. Materials and Methods: In this experimental study, using a gel injection device, BMMSCs were encapsulated in sodium alginate microcapsules containing 1.25% alginate, 1% gelatin, and four different concentrations of fibronectin (0.01, 0.05, 0.1, and 0.2 µg/ml). MTT assay was used to examine the proliferation of BMMSCs in des. Also, BMMSCs apoptosis rates were calculated using Annexin-V/PI staining and FACS analysis within 48 hours of exposure. Alkaline phosphatase (ALP) test was conducted to assess BMMSCs osteogenic differentiation. Finally, mRNA expression levels of the SP7, osteocalcin (OCN), Twist Family BHLH Transcription Factor 1 (Twist1), Peroxisome proliferator‐activated receptor γ2 (PPARγ2), Cyclin-dependent kinase 1 (CDK1), and Zinc Finger And BTB Domain Containing 16 (ZBTB16), which involved in MSCs differentiation process were evaluated using Real-Time PCR following exposure with fibronectin 0.1 µg/ml. Result: According to results, fibronectin had the potential to promote proliferation rates of the BMMSCs, in particular at 0.1 and 0.2 µg/ml concentrations. On the other hand, we showed that various concentrations of the fibronectin were not able to modify apoptosis rates of the BMMSCs, negatively or positively. Notable potential of the fibronectin, to trigger osteogenic differentiation of the BMMSCs was documented. Also, RT-PCR results indicated that fibronectin could augment osteogenic differentiation of cultured BMMSCs Conclusion: Results showed that fibronectin can improve proliferation and osteogenic differentiation of BMMSCs without any effect on these cells' survival.

scholarly journals Fisetin Induced Cell Death in Human Ovarian Cancer Cell Lines via ZBP1 Mediated Necroptosis.

2021 ◽  
Author(s):  
Yaxian Liu ◽  
Wenhong Cao ◽  
Yanhui Zhao ◽  
Lijuan Shan ◽  
Shuhai Lan
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cell Growth ◽  
Cell Lines ◽  
Annexin V ◽  
Dependent Manner ◽  
Apoptotic Process ◽  
Ovarian Cancer Cell Lines ◽  
And Migration

Abstract Background: Ovarian cancer leads to severe female mortality among all reproductive cancers. Fisetin, a natural flavonoid, exerts pharmacological characteristics on inhibiting cancer growth from various origins. Although multiple mechanisms involving in regulating cell death, there is still unclear if and how fisetin exhibits anti-cancer effect on ovarian cancer. The presented study aimed to evaluate cell apoptotic and necroptotic processes occurring in ovarian carcinoma (OC) cell lines induced by fisetin Methods: Cell growth was evaluated by MTT assay in both OC cell lines treated with or without fisetin. Annexin V/Propidium iodide staining followed by flow cytometry were used to characterize fisetin induced cell death. The apoptotic process was suppressed by z-VAD intervention then cell necroptosis was assessed by introducing ZBP1 knockdown OC cell lines coupled with fisetin intervention. The expression of necroptosis-related mediators and migration capability of respective cells were evaluated by western blotting and in vitro cell invasion assay. Result: Fisetin successfully reduced cell growth on both OC cell lines in a dose-dependent manner. Both apoptosis and necroptosis were induced by fisetin. Suppression on cell apoptotic process failed to enhance proliferation of fisetin treated cells. The induced cell death as well as robust expression of necroptotic markers RIP3 and MLKL were alleviated by knocking down the expression of ZBP1 protein in both OC cell lines.Conclusion: The present study demonstrated in vitro evidence supporting that both apoptosis and necroptosis were involved in fisetin induced OC cell death, while ZBP1 regulates necroptotic process via RIP3/MLKL pathway.

scholarly journals Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner

2017 ◽  
Vol 114 (43) ◽  
pp. 11500-11505 ◽  
Author(s):  
Hee Jung Yang ◽  
Jin Zhang ◽  
Wensheng Yan ◽  
Seong-Jun Cho ◽  
Christopher Lucchesi ◽  
...  
Keyword(s):  
Cell Growth ◽  
Inflammatory Diseases ◽  
Biological Significance ◽  
Mrna Translation ◽  
Mutant P53 ◽  
Dependent Manner ◽  
Cell Growth And Migration ◽  
P53 Expression ◽  
And Migration ◽  
In Cells

WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Nerve injury-induced protein 1 (Ninj1) is a target of p53 and forms a feedback loop with p53 by repressing p53 mRNA translation. Here, we show that loss of Ninj1 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of Ninj1 inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of Ninj1-deficient mice and found that Ninj1+/− mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of Ninj1 altered the tumor susceptibility in both mutant p53 and p53-null background. Specifically, in a mutant p53(R270H) background, Ninj1 deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a p53-null background, Ninj1 deficiency significantly increased the incidence of T-lymphoblastic lymphoma. Taken together, our data suggest that depending on p53 genetic status, Ninj1 has two opposing functions in tumorigenesis and that the Ninj1–p53 loop may be targeted to manage inflammatory diseases and cancer.

scholarly journals Inhibition of disulfide bonding of von Willebrand protein by monensin results in small, functionally defective multimers.

1985 ◽  
Vol 101 (1) ◽  
pp. 112-120 ◽  
Author(s):  
D D Wagner ◽  
T Mayadas ◽  
M Urban-Pickering ◽  
B H Lewis ◽  
V J Marder
Keyword(s):  
Molecular Weight ◽  
Endothelial Cells ◽  
Von Willebrand Disease ◽  
Low Molecular Weight ◽  
Dependent Manner ◽  
Experimental Conditions ◽  
The Matrix ◽  
High Concentrations ◽  
Von Willebrand ◽  
Processing Steps

The biosynthesis of von Willebrand protein by human endothelial cells was impaired by the presence of the carboxylic ionophore monensin. Several processing steps that have been localized to the Golgi apparatus were affected in a dose-dependent manner, including carbohydrate processing, dimer multimerization, and precursor cleavage. Since multimerization was more susceptible to the ionophore than was precursor cleavage, it appears that these processing steps are separate events. As expected, dimer formation, which occurs in the rough endoplasmic reticulum, was unaffected by monensin. Thus, at high concentrations of monensin, only dimer molecules were produced and secreted. The observed inhibition of multimer formation and precursor cleavage were not likely the result of incomplete carbohydrate processing, since inhibition of complex carbohydrate formation by swainsonine did not interfere with the other processing steps. Monensin also affected the capacity of endothelial cells to store von Willebrand protein, as the ratio of secreted to cell-associated protein increased dramatically in the presence of monensin, and the processed forms could not be found in the treated cells. The low molecular weight multimers produced in the presence of monensin did not incorporate in the endothelial cells' extracellular matrix nor did they bind to the matrix of human foreskin fibroblasts. In summary, the presence of monensin in human endothelial cell culture produced experimental conditions that mimic Type IIA von Willebrand disease, in that the cells synthesized and secreted only low molecular weight von Willebrand protein multimers, which were functionally defective.

Neutrophil Elastase Potentiates Cathepsin G-lnduced Platelet Activation

1992 ◽  
Vol 68 (05) ◽  
pp. 570-576 ◽  
Author(s):  
Mary A Selak
Keyword(s):  
Neutrophil Elastase ◽  
Cell Activation ◽  
Thromboxane A2 ◽  
Creatine Phosphate ◽  
Dense Granule ◽  
Cathepsin G ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Low Concentrations ◽  
High Concentrations

SummaryWe have previously demonstrated that human neutrophil cathepsin G is a strong platelet agonist that binds to a specific receptor. This work describes the effect of neutrophil elastase on cathepsin G-induced platelet responses. While platelets were not activated by high concentrations of neutrophil elastase by itself, elastase enhanced aggregation, secretion and calcium mobilization induced by low concentrations of cathepsin G. Platelet aggregation and secretion were potentiated in a concentration-dependent manner by neutrophil elastase with maximal responses observable at 200 nM. Enhancement was observed when elastase was preincubated with platelets for time intervals of 10–60 s prior to addition of a low concentration of cathepsin G and required catalytically-active elastase since phenylmethanesulphonyl fluoride-inhibited enzyme failed to potentiate cell activation. Neutrophil elastase potentiation of platelet responses induced by low concentrations of cathepsin G was markedly inhibited by creatine phosphate/creatine phosphokinase and/or indomethacin, indicating that the synergism between elastase and cathepsin G required the participation of ADP and thromboxane A2. On the other hand, platelet responses were not attenuated by the PAF antagonist BN 52021, signifying that PAF-acether did not play a role in elastase potentiation. At higher concentrations porcine pancreatic elastase exhibits similar effects to neutrophil elastase, demonstrating that the effect of elastase was not unique to the neutrophil protease. While neutrophil elastase failed to alter the ability of cathepsin G to hydrolyze a synthetic chromogenic substrate, preincubation of platelets with elastase increased the apparent affinity of cathepsin G binding to platelets. In contrast to their effect on cathepsin G-induced platelet responses, neither neutrophil nor pancreatic elasatse potentiated aggregation or dense granule release initiated by ADP, PAF-acether, arachidonic acid or U46619, a thromboxane A2 mimetic. Moreover, unlike its effect on cathepsin G, neutrophil elastase inhibited thrombin-induced responses. The current observations demonstrate that elastase can potentiate platelet responses mediated by low concentrations of cathepsin G, suggesting that both enzymes may function synergistically to activate platelets under conditions where neutrophil degranulation occurs.

Increased Procoagulant Activity of Red Blood Cells from Patients with Homozygous Sickle Cell Disease and β-Thalassemia

1996 ◽  
Vol 76 (03) ◽  
pp. 322-327 ◽  
Author(s):  
Dominique Helley ◽  
Amiram Eldor ◽  
Robert Girot ◽  
Rolande Ducrocq ◽  
Marie-Claude Guillin ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Sickle Cell ◽  
Blood Cells ◽  
Annexin V ◽  
Mean Value ◽  
Procoagulant Activity ◽  
Dependent Manner ◽  
Cell Disease ◽  
Homozygous Sickle Cell Disease

SummaryIt has recently been proved that, in vitro, red blood cells (RBCs) from patients with homozygous β-thalassemia behave as procoagulant cells. The procoagulant activity of β-thalassemia RBCs might be the result of an increased exposure of procoagulant phospholipids (i. e. phosphatidylserine) in the outer leaflet of the membrane. In order to test this hypothesis, we compared the catalytic properties of RBCs of patients with β-thalassemia and homozygous sickle cell disease (SS-RBCs) with that of controls. The catalytic parameters (Km, kcat) of prothrombin activation by factor Xa were determined both in the absence and in the presence of RBCs. The turn-over number (kcat) of the reaction was not modified by normal, SS- or (3-thalassemia RBCs. The Km was lower in the presence of normal RBCs (mean value: 9.1 µM) than in the absence of cells (26 µM). The Km measured in the presence of either SS-RBCs (mean value: 1.6 µM) or β-thalassemia RBCs (mean value: 1.5 pM) was significantly lower compared to normal RBCs (p <0.001). No significant difference was observed between SS-RBCs and p-thalassemia RBCs. Annexin V, a protein with high affinity and specificity for anionic phospholipids, inhibited the procoagulant activity of both SS-RBCs and (3-thalassemia RBCs, in a dose-dependent manner. More than 95% inhibition was achieved at nanomolar concentrations of annexin V. These results indicate that the procoagulant activity of both β-thalassemia RBCs and SS-RBCs may be fully ascribed to an abnormal exposure of phosphatidylserine at the outer surface of the red cells.

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