scholarly journals Embelin as a Novel Inhibitor of PKC in the Prevention of Platelet Activation and Thrombus Formation

2019 ◽  
Vol 8 (10) ◽  
pp. 1724 ◽  
Author(s):  
Jiun Yi Li ◽  
Ray Jade Chen ◽  
Li Ting Huang ◽  
Tzu Yin Lee ◽  
Wan Jung Lu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Therapeutic Potential ◽  
Thrombus Formation ◽  
Biological Activities ◽  
Mitogen Activated Protein Kinase ◽  
Antitumor Effects ◽  
Pkc Inhibitor ◽  
Downstream Signaling ◽  
Embelia Ribes ◽  
Mitogen Activated Protein

Embelin is a quinone derivative and found in the fruits of Embelia ribes Burm.f. Embelin has been identified as a small molecular inhibitor of X-chromosome-linked inhibitor of apoptosis proteins, and has multiple biological activities, including antioxidation, anti-inflammation, and antitumor effects. However, the effect of embelin in platelets remains unclear. Thus, this study investigated the antiplatelet mechanism of embelin. Our data revealed that embelin could inhibit platelet aggregation induced by various agonists, including the protein kinase C (PKC) activator phorbol 12,13-dibutyrate (PDBu). Embelin, as well as the PKC inhibitor Ro 31-8220, markedly reduced PDBu-mediated phosphorylation of the PKC substrate, suggesting that embelin may be a PKC inhibitor for platelets. Embelin could block PKC downstream signaling and events, including the inhibition of protein kinase B and mitogen-activated protein kinase activation, granule release, and glycoprotein IIbIIIa activation. Moreover, embelin could delay thrombus formation in the mesenteric microvessels of mice, but did not significantly affect the tail bleeding time. In conclusion, we demonstrated that embelin is a PKC inhibitor and possesses antiplatelet and antithrombotic effects. The further analysis is necessary to more accurately determine clinical therapeutic potential of embelin in all clinical thromboembolic events with disturbance of thrombocyte function.

Role of p38 Mitogen-Activated Protein Kinase in Thrombus Formation

2004 ◽  
Vol 24 (4) ◽  
pp. 283-296 ◽  
Author(s):  
Kanako Sakurai ◽  
Yuji Matsuo ◽  
Tatsuhiko Sudo ◽  
Yoh Takuwa ◽  
Sadao Kimura ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Thrombus Formation ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

scholarly journals Xanthohumol, a Prenylated Flavonoid from Hops (Humulus lupulus), Prevents Platelet Activation in Human Platelets

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Ye-Ming Lee ◽  
Kuo-Hsien Hsieh ◽  
Wan-Jung Lu ◽  
Hsiu-Chu Chou ◽  
Duen-Suey Chou ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Protein Kinase ◽  
Platelet Activation ◽  
Therapeutic Potential ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Humulus Lupulus ◽  
Mitogen Activated Protein Kinase ◽  
Akt Phosphorylation ◽  
Mitogen Activated Protein

Xanthohumol is the principal prenylated flavonoid in the hop plant (Humulus lupulusL.). Xanthohumol was found to be a very potent cancer chemopreventive agent through regulation of diverse mechanisms. However, no data are available concerning the effects of xanthohumol on platelet activation. The aim of this paper was to examine the antiplatelet effect of xanthohumol in washed human platelets. In the present paper, xanthohumol exhibited more-potent activity in inhibiting platelet aggregation stimulated by collagen. Xanthohumol inhibited platelet activation accompanied by relative [Ca2+]imobilization, thromboxane A2formation, hydroxyl radical (OH●) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and Akt phosphorylation. Neither SQ22536, an inhibitor of adenylate cyclase, nor ODQ, an inhibitor of guanylate cyclase, reversed the xanthohumol-mediated inhibitory effect on platelet aggregation. Furthermore, xanthohumol did not significantly increase nitrate formation in platelets. This study demonstrates for the first time that xanthohumol possesses potent antiplatelet activity which may initially inhibit the PI3-kinase/Akt, p38 MAPK, and PLCγ2-PKC cascades, followed by inhibition of the thromboxane A2formation, thereby leading to inhibition of [Ca2+]iand finally inhibition of platelet aggregation. Therefore, this novel role of xanthohumol may represent a high therapeutic potential for treatment or prevention of cardiovascular diseases.

scholarly journals Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase

1993 ◽  
Vol 90 (23) ◽  
pp. 10952-10956 ◽  
Author(s):  
R H Chen ◽  
C Abate ◽  
J Blenis
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
S6 Kinase ◽  
Downstream Signaling ◽  
C Terminus ◽  
Mitogen Activated Protein ◽  
Ribosomal S6 Kinase

Phosphorylation of the C terminus of c-Fos has been implicated in serum response element-mediated repression of c-fos transcription after its induction by serum growth factors. The growth-regulated enzymes responsible for this phosphorylation in early G1 phase of the cell cycle and the sites of phosphorylation have not been identified. We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kDa ribosomal S6 kinase (RSK) and mitogen-activated protein kinase (MAP kinase), contribute to the serum-induced phosphorylation of c-Fos. The major phosphopeptides derived from biosynthetically labeled c-Fos correspond to phosphopeptides generated after phosphorylation of c-Fos in vitro with both RSK and MAP kinase. The phosphorylation sites identified for RSK (Ser-362) and MAP kinase (Ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear RSK and MAP kinase in modulating newly synthesized c-Fos phosphorylation and downstream signaling.

Zerumbone Reduces the Level of MAPK1 by Upregulating Mir-758-3p to Inhibit the Survival of Thyroid Papillary Cancer Cells

2020 ◽  
Vol 18 (4) ◽  
pp. 378-385
Author(s):  
Huling Wen ◽  
Zhengmin Xu ◽  
Dan Wen ◽  
Shiyu Lin ◽  
Yu Liang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Papillary Carcinoma ◽  
Lentiviral Vector ◽  
Therapeutic Potential ◽  
Thyroid Papillary Carcinoma ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Assay ◽  
Protective Effects ◽  
Thyroid Papillary ◽  
Mitogen Activated Protein

Thyroid papillary carcinoma is the most common type of thyroid malignancy. The mitogen-activated protein kinase signaling cascade is the major pathway involved in thyroid papillary carcinoma and may be regulated by small molecules and transcription factors. Zerumbone is a bioactive compound with multiple pharmacological properties. This study investigated the effects of zerumbone on survival and proliferation of thyroid papillary carcinoma-1 cells with an emphasis on the level of microRNA-758-3p and its target gene, mitogen-activated protein kinase-1. Zerumbone exhibited dose-dependent inhibitory effects on the viability and proliferation of thyroid papillary carcinoma-1 cells. It also gradually elevated the level of microRNA-758-3p but decreased mitogen-activated protein kinase-1 expression in these cells. Mitogen-activated protein kinase-1 has been suggested as a downstream target of microRNA-758-3p and confirmed by dual-reporter luciferase assay. The downregulation of microRNA-758-3p in thyroid papillary carcinoma-1 cells via the transfection with microRNA-758-3p inhibitor reversed the inhibitory effect of zerumbone on mitogen-activated protein kinase-1 expression. Furthermore, the transfection of thyroid papillary carcinoma-1 cells with lentiviral vector overexpressing mitogen-activated protein kinase-1 eliminated the protective effects of zerumbone on thyroid papillary carcinoma progression as compared to the group delivered with control vector. In conclusion, this study demonstrated that zerumbone inhibited survival and proliferation of thyroid papillary carcinoma-1 cells via suppressing the expression of mitogen-activated protein kinase-1 through microRNA-758-3p. These data suggest the therapeutic potential of zerumbone in thyroid papillary carcinoma treatment.

scholarly journals Involvement of the Mitogen-activated Protein Kinase c-Jun NH2-terminal Kinase 1 in Thrombus Formation

2007 ◽  
Vol 282 (44) ◽  
pp. 31990-31999 ◽  
Author(s):  
Alexandre Kauskot ◽  
Frédéric Adam ◽  
Alexandra Mazharian ◽  
Nadine Ajzenberg ◽  
Eliane Berrou ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Thrombus Formation ◽  
Mitogen Activated Protein Kinase ◽  
Kinase C ◽  
Mitogen Activated Protein

scholarly journals Canagliflozin protects against sepsis capillary leak syndrome by activating endothelial α1AMPK

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marine Angé ◽  
Julien De Poortere ◽  
Audrey Ginion ◽  
Sylvain Battault ◽  
Mélanie Dechamps ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Kinase ◽  
Therapeutic Potential ◽  
Capillary Leak Syndrome ◽  
Mitogen Activated Protein Kinase ◽  
Capillary Leak ◽  
Albumin Leakage ◽  
Mitogen Activated Protein ◽  
Dependent Pathway

AbstractSepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad’s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.

scholarly journals Is Emodin with Anticancer Effects Completely Innocent? Two Sides of the Coin

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2733
Author(s):  
Esra Küpeli Akkol ◽  
Iffet Irem Tatlı ◽  
Gökçe Şeker Karatoprak ◽  
Osman Tuncay Ağar ◽  
Çiğdem Yücel ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Reproductive Toxicity ◽  
Natural Compounds ◽  
The Body ◽  
Mitogen Activated Protein Kinase ◽  
Drug Candidates ◽  
Mitogen Activated Protein

Many anticancer active compounds are known to have the capacity to destroy pathologically proliferating cancer cells in the body, as well as to destroy rapidly proliferating normal cells. Despite remarkable advances in cancer research over the past few decades, the inclusion of natural compounds in researches as potential drug candidates is becoming increasingly important. However, the perception that the natural is reliable is an issue that needs to be clarified. Among the various chemical classes of natural products, anthraquinones have many biological activities and have also been proven to exhibit a unique anticancer activity. Emodin, an anthraquinone derivative, is a natural compound found in the roots and rhizomes of many plants. The anticancer property of emodin, a broad-spectrum inhibitory agent of cancer cells, has been detailed in many biological pathways. In cancer cells, these molecular mechanisms consist of suppressing cell growth and proliferation through the attenuation of oncogenic growth signaling, such as protein kinase B (AKT), mitogen-activated protein kinase (MAPK), HER-2 tyrosine kinase, Wnt/-catenin, and phosphatidylinositol 3-kinase (PI3K). However, it is known that emodin, which shows toxicity to cancer cells, may cause kidney toxicity, hepatotoxicity, and reproductive toxicity especially at high doses and long-term use. At the same time, studies of emodin, which has poor oral bioavailability, to transform this disadvantage into an advantage with nano-carrier systems reveal that natural compounds are not always directly usable compounds. Consequently, this review aimed to shed light on the anti-proliferative and anti-carcinogenic properties of emodin, as well as its potential toxicities and the advantages of drug delivery systems on bioavailability.

scholarly journals Involvement of Mitogen-Activated Protein Kinase Pathways in Interleukin-8 Production by Human Monocytes and Polymorphonuclear Cells Stimulated with Lipopolysaccharide or Mycoplasma fermentans Membrane Lipoproteins

1999 ◽  
Vol 67 (2) ◽  
pp. 688-693 ◽  
Author(s):  
Christelle Marie ◽  
Sergio Roman-Roman ◽  
Georges Rawadi
Keyword(s):  
Protein Kinase ◽  
Protein Tyrosine Kinase ◽  
Human Monocyte ◽  
Interleukin 8 ◽  
Mitogen Activated Protein Kinase ◽  
Polymorphonuclear Cells ◽  
Mycoplasma Fermentans ◽  
Downstream Signaling ◽  
Inflammatory Stimuli ◽  
Mitogen Activated Protein

ABSTRACT Interleukin-8 (IL-8) is a chemokine that belongs to the α-chemokine or CXC subfamily and is produced by a wide variety of human cells, including monocytes and polymorphonuclear cells (PMN). IL-8 is secreted in response to inflammatory stimuli, notably bacterial products such as lipopolysaccharide (LPS), but little is known about the mechanisms by which these agents mediate IL-8 induction. In this report, we show that Mycoplasma fermentans lipid-associated membrane proteins (LAMPf) induce the production of high levels of IL-8 by THP-1 (human monocyte) cells and PMN at the same extent as LPS. It was previously demonstrated that stimulation of monocytic cells with either LPS or LAMPf led to a series of common downstream signaling events, including the activation of protein tyrosine kinase and of mitogen-activated protein kinase cascades. By using PD-98059 and SB203580, two potent and selective inhibitors of MEK1 (a kinase upstream of ERK1/2) and p38, respectively, we have demonstrated that both ERK1/2 and p38 cascades play a key role in the production of IL-8 by monocytes and PMN stimulated with bacterial fractions.

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