scholarly journals Novel Antidepressant-Like Activity of Caffeic Acid Phenethyl Ester Is Mediated by Enhanced Glucocorticoid Receptor Function in the Hippocampus

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Mi-Sook Lee ◽  
Young Han Kim ◽  
Bo-ram Lee ◽  
Seung-Hae Kwon ◽  
Won-Jin Moon ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Caffeic Acid ◽  
Behavioral Assessment ◽  
Caffeic Acid Phenethyl Ester ◽  
Mitogen Activated Protein Kinase ◽  
Antidepressant Effect ◽  
Chronic Unpredictable Stress ◽  
Western Blots ◽  
Corticosterone Secretion ◽  
Mitogen Activated Protein

Caffeic acid phenethyl ester (CAPE) is an active component of propolis that has a variety of potential pharmacological effects. Although we previously demonstrated that propolis has antidepressant-like activity, the effect of CAPE on this activity remains unknown. The present study assessed whether treatment with CAPE (5, 10, and 20 µmol/kg for 21 days) has an antidepressant-like effect in mice subjected to chronic unpredictable stress via tail suspension (TST) and forced swim (FST) tests. CAPE administration induced behaviors consistent with an antidepressant effect, evidenced by decreased immobility in the TST and FST independent of any effect on serum corticosterone secretion. Western blots, conducted subsequent to behavioral assessment, revealed that CAPE significantly decreased glucocorticoid receptor phosphorylation at S234 (pGR(S234)), resulting in an increased pGR(S220/S234) ratio. We also observed negative correlations between pGR(S220)/(S234) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation, which was decreased by CAPE treatment. These findings suggest that CAPE treatment exerts an antidepressant-like effect via downregulation of p38MAPK phosphorylation, thereby contributing to enhanced GR function.

Mitogen-activated protein kinase mediation of hemolysate-induced contraction in rabbit basilar artery

1999 ◽  
Vol 90 (6) ◽  
pp. 1091-1097 ◽  
Author(s):  
Alexander Y. Zubkov ◽  
Kotaro Ogihara ◽  
Phani Tumu ◽  
Anita Patlolla ◽  
Adam I. Lewis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Basilar Artery ◽  
Kinase Inhibitor ◽  
Contractile Response ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Western Blots ◽  
Content Type ◽  
Mitogen Activated Protein ◽  
Fine Print

Object. Mitogen-activated protein kinase (MAPK) is an important signaling factor in vascular proliferation and contraction, which are the two features of cerebral vasospasm that follow subarachnoid hemorrhage. The authors studied the possible involvement of MAPK in hemolysate-induced signal transduction and contraction in rabbit basilar artery (BA).Methods. Isometric tension was used to record the contractile response of rabbit BA to hemolysate, and Western blots were obtained using antibodies for MAPK.The following results are reported. 1) Hemolysate produced a concentration-dependent contraction of rabbit BA; however, preincubation of arteries with the MAPK kinase (MEK) inhibitor PD-98059 markedly reduced this contraction. The administration of PD-98059 also relaxed, in a concentration-dependent fashion, the sustained contraction induced by 10% hemolysate. 2) The Janus tyrosine kinase 2 inhibitor AG-490, preincubated with arterial rings, reduced the contractile response to hemolysate but failed to relax the sustained contraction induced by this agent. The Src-tyrosine kinase inhibitor damnacanthal and the phosphatidylinositol 3—kinase inhibitor wortmannin failed to reduce hemolysate-induced contraction. 3) Hemolysate produced a time-dependent elevation of MAPK immunoreactivity as seen on Western blots of rabbit BA. The MAPK was enhanced 1 minute after hemolysate exposure and the effect reached maximum levels at 5 minutes. The immunoreactivity of MAPK decayed slowly over time, but the level of this kinase was still higher than the basal level, even at 2 hours after exposure to hemolysate. Preincubation of arteries with the MEK inhibitor PD-98059 abolished the effect of hemolysate on MAPK immunoreactivity.Conclusions. Hemolysate produced contraction of rabbit BA, possibly by activation of MAPK, and therefore MAPK inhibitors may be useful in the treatment of cerebral vasospasm.

scholarly journals Site-Specific Phosphorylation Induces Functionally Active Conformation in the Intrinsically Disordered N-Terminal Activation Function (AF1) Domain of the Glucocorticoid Receptor

2009 ◽  
Vol 30 (1) ◽  
pp. 220-230 ◽  
Author(s):  
Anna M. S. Garza ◽  
Shagufta H. Khan ◽  
Raj Kumar
Keyword(s):  
Glucocorticoid Receptor ◽  
Tertiary Structure ◽  
Steroid Receptors ◽  
Activation Function ◽  
Mitogen Activated Protein Kinase ◽  
Active Conformation ◽  
Activation Domain ◽  
Site Specific ◽  
Intrinsically Disordered ◽  
Mitogen Activated Protein

ABSTRACT Intrinsically disordered (ID) regions are disproportionately higher in cell signaling proteins and are predicted to have much larger frequency of phosphorylation sites than ordered regions, suggesting an important role in their regulatory capacity. In this study, we show that AF1, an ID activation domain of the glucocorticoid receptor (GR), adopts a functionally folded conformation due to its site-specific phosphorylation by p38 mitogen-activated protein kinase, which is involved in apoptotic and gene-inductive events initiated by the GR. Further, we show that site-specific phosphorylation-induced secondary and tertiary structure formation specifically facilitates AF1's interaction with critical coregulatory proteins and subsequently its transcriptional activity. These data demonstrate a mechanism through which ID activation domain of the steroid receptors and other similar transcription factors may adopt a functionally active conformation under physiological conditions.

scholarly journals Caffeic Acid Inhibits RANKL and TNFa-induced Osteoclastogenesis by Targeting TAK1-p44/42 MAPK

2021 ◽  
Vol 13 (4) ◽  
pp. 433-7
Author(s):  
Ferry Sandra ◽  
Jennifer Putri ◽  
Hilary Limen ◽  
Blanca Sarizta
Keyword(s):  
Caffeic Acid ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Raw264.7 Cells ◽  
Tartrate Resistant Acid Phosphatase ◽  
Receptor Activator ◽  
Mitogen Activated Protein ◽  
Pre Treatment ◽  
Necrosis Factor

BACKGROUND: The potential of the caffeic acid in other important Receptor Activator Nuclear Factor kB Ligand (RANKL)-Tumor Necrosis Factor (TNF)a-induced osteoclastogenic signaling pathways has not been known. Therefore, the current study was conducted to explore as well as to understand the inhibition potential of caffeic acid.METHODS: RAW264.7 cells were cultured, treated with caffeic acid, RANKL and TNFa. Tartrate Resistant Acid Phosphatase (TRAP) staining was performed to detect TRAP+ osteoclast-like polynuclear cells. To detect the activity of p44/42 Mitogen Activated Protein Kinase (MAPK), Akt, and Transforming Growth Factor-β-activated Kinase (TAK)1, the phosphorylated forms of the proteins were investigated with the immunoblotting assay.RESULTS: Pre-treatment of caffeic acid inhibited the RANKL and TNFa-induced differentiation of RAW264.7 cells into TRAP+ osteoclast-like polynuclear cells. RANKL and TNFa induced phosphorylation of p44/42 MAPK at Thr202/Tyr204, phosphorylation of Akt at both Ser473 and Thr308 and phosphorylation of TAK1 at Ser412. Pre-treatment with caffeic acid prior to the RANKL and TNFa induction, inhibited the phosphorylation of MAPK, and TAK1, but not Akt.CONCLUSION: Caffeic acid might regulate the RANKL-TNFa-induced osteoclastogenic pathway in RAW264.7 by targeting TAK1, which later activation of p44/42 MAPK was abolished.KEYWORDS: caffeic acid, osteoclastogenesis, p44/42, Erk1/2, Akt, TAK1, RAW264.7 

scholarly journals Selective knockdown of AT1 receptors by RNA interference inhibits Val5-ANG II endocytosis and NHE-3 expression in immortalized rabbit proximal tubule cells

2007 ◽  
Vol 293 (1) ◽  
pp. C367-C378 ◽  
Author(s):  
Xiao C. Li ◽  
Jia L. Zhuo
Keyword(s):  
Proximal Tubule ◽  
Physiological Effect ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Protein ◽  
Proximal Tubule Cell ◽  
Ang Ii ◽  
Western Blots ◽  
Receptor Mediated Endocytosis ◽  
Mitogen Activated Protein

Receptor-mediated endocytosis of extracellular ANG II has been suggested to play an important role in the regulation of proximal tubule cell (PTC) function. Using immortalized rabbit PTCs as an in vitro cell culture model, we tested the hypothesis that extracellular ANG II is taken up by PTCs through angiotensin type 1 receptor (AT1; or AT1a) receptor-mediated endocytosis and that inhibition of ANG II endocytosis using a selective AT1 receptor small-interfering RNA (siRNA; AT1R siRNA) or endocytotic inhibitors exerts a physiological effect on total and apical sodium and hydrogen exchanger isoform 3 (NHE-3) protein abundance. Western blots and live cell imaging with FITC-labeled ANG II confirmed that transfection of PTCs with a human specific AT1R siRNA for 48 h selectively knocked down AT1 receptor protein by 76 ± 5% ( P < 0.01), whereas transfection with a scrambled siRNA had little effect. In nontransfected PTCs, exposure to extracellular ANG II (1 nM) for 60 min at 37°C increased intracellular ANG II accumulation by 67% (control: 566 ± 55 vs. ANG II: 943 ± 160 pg/mg protein, P < 0.05) and induced mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (163 ± 15% of control, P < 0.01). AT1R siRNA reduced ANG II endocytosis to a level similar to losartan, which blocks cell surface AT1 receptors (557 ± 37 pg/mg protein, P < 0.05 vs. ANG II), or to colchicine, which disrupts cytoskeleton microtubules (613 ± 12 pg/mg protein, P < 0.05 vs. ANG II). AT1R siRNA, losartan, and colchicine all attenuated ANG II-induced ERK1/2 activation and total cell lysate and apical membrane NHE-3 abundance. The scrambled siRNA had no effect on ANG II endocytosis, ERK1/2 activation, or NHE-3 expression. These results suggest that AT1 receptor-mediated endocytosis of extracellular ANG II may regulate proximal tubule sodium transport by increasing total and apical NHE-3 proteins.

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