scholarly journals Chemoreactome analysis of 7-hydroxymatairesinol, 17-estradiol, phytoestrogen β-sitosterol and epigallocatechin-3-gallate

2020 ◽  
Vol 14 (3) ◽  
pp. 347-360
Author(s):  
I. Yu. Torshin ◽  
A. N. Rubashkina ◽  
N. P. Lapochkina ◽  
O. A. Gromova
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Molecular Mechanisms ◽  
Leukotriene B4 ◽  
Antioxidant Effect ◽  
Pharmacological Effects ◽  
Cyclin Dependent Kinases ◽  
Prostacyclin Receptor ◽  
Viral Proteases ◽  
Leukotriene B4 Receptor

The results of the evaluation of 7-hydroximatairesinol (7-HMR) properties in comparison with control molecules (17-estradiol, phytoestrogen β-sytostirol, epigallocatechin-3-gallate) are presented. The results of chemoreactomic modeling allowed to formulate the molecular mechanisms of 7-HMR pharmacological effects for anti-inflammatory (inhibition of 5-lipoxygenase, matrix metalloproteinase MMR2, mitogen-activated kinase p38-alpha, leukotriene-b4 receptor, prostacyclin receptor), antitumor (antioxidant effect due to inhibition of hemoxygenase-2, inhibition of cyclin dependent kinases 3 and 4, epidermis growth factor, protein mTOR), vasodilator (inhibition of adrenoreceptors and renin), antibacterial and antiviral (inhibition of viral proteases 3C) properties of 7-HMR molecule.

Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1933-1939 ◽  
Author(s):  
Tarja Jonuleit ◽  
Heiko van der Kuip ◽  
Cornelius Miething ◽  
Heike Michels ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Down Regulation ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Abl Kinase

Abstract Chronic myeloid leukemia (CML) is a malignant stem cell disease characterized by an expansion of myeloid progenitor cells expressing the constitutively activated Bcr-Abl kinase. This oncogenic event causes a deregulation of apoptosis and cell cycle progression. Although the molecular mechanisms protecting from apoptosis in CML cells are well characterized, the cell cycle regulatory event is poorly understood. An inhibitor of the cyclin-dependent kinases, p27, plays a central role in the regulation of growth factor dependent proliferation of hematopoietic cells. Therefore, we have analyzed the influence of Bcr-Abl in the regulation of p27 expression in various hematopoietic cell systems. An active Bcr-Abl kinase causes down-regulation of p27 expression in murine Ba/F3 cells and human M07 cells. Bcr-Abl blocks up-regulation of p27 after growth factor withdrawal and serum reduction. In addition, p27 induction by transforming growth factor-beta (TGF-β) is completely blocked in Bcr-Abl positive M07/p210 cells. This deregulation is directly mediated by the activity of the Bcr-Abl kinase. A Bcr-Abl kinase inhibitor completely abolishes p27 down-regulation by Bcr-Abl in both Ba/F3 cells transfected either with a constitutively active Bcr-Abl or with a temperature sensitive mutant. The down-regulation of p27 by Bcr-Abl depends on proteasomal degradation and can be blocked by lactacystin. Overexpression of wild-type p27 partially antagonizes Bcr-Abl–induced proliferation in Ba/F3 cells. We conclude that Bcr-Abl promotes cell cycle progression and activation of cyclin-dependent kinases by interfering with the regulation of the cell cycle inhibitory protein p27.

Bcr-Abl kinase down-regulates cyclin-dependent kinase inhibitor p27 in human and murine cell lines

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1933-1939 ◽  
Author(s):  
Tarja Jonuleit ◽  
Heiko van der Kuip ◽  
Cornelius Miething ◽  
Heike Michels ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Down Regulation ◽  
Cycle Progression ◽  
Cyclin Dependent Kinases ◽  
Abl Kinase

Chronic myeloid leukemia (CML) is a malignant stem cell disease characterized by an expansion of myeloid progenitor cells expressing the constitutively activated Bcr-Abl kinase. This oncogenic event causes a deregulation of apoptosis and cell cycle progression. Although the molecular mechanisms protecting from apoptosis in CML cells are well characterized, the cell cycle regulatory event is poorly understood. An inhibitor of the cyclin-dependent kinases, p27, plays a central role in the regulation of growth factor dependent proliferation of hematopoietic cells. Therefore, we have analyzed the influence of Bcr-Abl in the regulation of p27 expression in various hematopoietic cell systems. An active Bcr-Abl kinase causes down-regulation of p27 expression in murine Ba/F3 cells and human M07 cells. Bcr-Abl blocks up-regulation of p27 after growth factor withdrawal and serum reduction. In addition, p27 induction by transforming growth factor-beta (TGF-β) is completely blocked in Bcr-Abl positive M07/p210 cells. This deregulation is directly mediated by the activity of the Bcr-Abl kinase. A Bcr-Abl kinase inhibitor completely abolishes p27 down-regulation by Bcr-Abl in both Ba/F3 cells transfected either with a constitutively active Bcr-Abl or with a temperature sensitive mutant. The down-regulation of p27 by Bcr-Abl depends on proteasomal degradation and can be blocked by lactacystin. Overexpression of wild-type p27 partially antagonizes Bcr-Abl–induced proliferation in Ba/F3 cells. We conclude that Bcr-Abl promotes cell cycle progression and activation of cyclin-dependent kinases by interfering with the regulation of the cell cycle inhibitory protein p27.

scholarly journals Effect of Caffeic Acid Phenethyl Ester Provision on Fibroblast Growth Factor-2, Matrix Metalloproteinase-9 Expression, Osteoclast and Osteoblast Numbers during Experimental Tooth Movement in Wistar Rats (Rattus norvegicus)

2021 ◽  
Author(s):  
Ida Bagus Narmada ◽  
Paristyawati Dwi Putri ◽  
Lucky Lucynda ◽  
Ari Triwardhani ◽  
I Gusti Aju Wahju Ardani ◽  
...  
Keyword(s):  
Growth Factor ◽  
Matrix Metalloproteinase ◽  
Rattus Norvegicus ◽  
Wistar Rats ◽  
Tooth Movement ◽  
Caffeic Acid Phenethyl Ester ◽  
Fibroblast Growth Factor 2 ◽  
Fibroblast Growth ◽  
Male Wistar Rats ◽  
Metalloproteinase 9

Abstract Objectives To investigate the effect of caffeic acid phenethyl ester (CAPE) provision on matrix metalloproteinase-9 (MMP-9), fibroblast growth factor-2 (FGF-2) expression, osteoclast and osteoblast numbers during experimental orthodontic tooth movement (OTM) in male Wistar rats (Rattus norvegicus). Materials and Methods Forty-eight healthy male Wistar rats (R. norvegicus), 16 to 20 weeks old with 200 to 250 g body weight (bw) were divided into several groups as follows: K1: OTM for 3 days; K2: OTM for 7 days; K3: OTM for 14 days; KP1: OTM and CAPE for 3 days; KP2: OTM and CAPE for 7 days; and KP3: OTM and CAPE for 14 days. A nickel titanium closed coil spring 8.0 mm long with 10 g/mm2 was installed between the upper left first molar and upper central incisor to move molar mesially. CAPE provision with a dose of 20 mg/kg bw of animal studies was done per orally. Immunohistochemistry was done to examine MMP-9 expression and osteoclast number in compression side as well as FGF-2 expression and osteoblast number in tensile side of the OTM. Statistical Analysis One-way analysis of variance test and Tukey’s honest significant difference test were performed to determine the difference between the groups (p < 0.05). Results MMP-9 expression and osteoclast numbers in the compression side were significantly different between the groups. Similarly, FGF-2 expression and osteoclast numbers in the tensile side were significantly different between the groups. Conclusions CAPE provision during OTM increases the number of osteoblasts and the FGF-2 expression significantly in the tensile side. Osteoclast numbers and MMP-9 expression significantly decrease in the compression side.

scholarly journals Targeting fibroblast growth factor receptors to combat aggressive ependymoma

2021 ◽  
Author(s):  
Daniela Lötsch ◽  
Dominik Kirchhofer ◽  
Bernhard Englinger ◽  
Li Jiang ◽  
Konstantin Okonechnikov ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Molecular Mechanisms ◽  
Radial Glia ◽  
Growth Factor Receptors ◽  
Dominant Negative ◽  
Mrna Levels ◽  
Fibroblast Growth ◽  
Cell Models ◽  
Fibroblast Growth Factor Receptors

AbstractEpendymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.

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