Theobromine, the Primary Methylxanthine Found inTheobroma cacao, Prevents Malignant Glioblastoma Proliferation by Negatively Regulating Phosphodiesterase-4, Extracellular Signal-regulated Kinase, Akt/mammalian Target of Rapamycin Kinase, and Nuclear Factor-Kappa B

2014 ◽  
Vol 66 (3) ◽  
pp. 419-423 ◽  
Author(s):  
Naotoshi Sugimoto ◽  
Shinji Miwa ◽  
Yoshiaki Hitomi ◽  
Hiroyuki Nakamura ◽  
Hiroyuki Tsuchiya ◽  
...  
Keyword(s):  
Nuclear Factor Kappa B ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Nuclear Factor ◽  
Extracellular Signal Regulated Kinase ◽  
Phosphodiesterase 4 ◽  
Nuclear Factor Kappa ◽  
Extracellular Signal

scholarly journals Periplaneta americana Extracts Promote Skin Wound Healing via Nuclear Factor Kappa B Canonical Pathway and Extracellular Signal-Regulated Kinase Signaling

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Qin Song ◽  
Qiheng Gou ◽  
Yuxin Xie ◽  
Zhen Zhang ◽  
Chaomei Fu
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Periplaneta Americana ◽  
Nuclear Factor Kappa B ◽  
Nuclear Translocation ◽  
Nuclear Factor ◽  
Protective Function ◽  
Extracellular Signal Regulated Kinase ◽  
Nuclear Factor Kappa ◽  
Extracellular Signal

Periplaneta americana extracts (PAEs) exhibit wound healing properties. However, the underlying molecular mechanisms are not well understood. Here, we treated human skin fibroblasts (HSF) with PAE and the proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The wound healing and transwell migration assays were used to detect cell migration. Nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) pathways were analyzed by Western blot (WB). Immunofluorescence staining was used to detect the key molecular localization in the cells. The results showed that PAE enhanced the proliferation and migration of HSF cells. The expression and activation of key proteins such as RelA and p-ERK were increased in NF-κB and ERK pathways followed by nuclear translocation. In vivo, both WB and immunohistochemical (IHC) staining showed that PAE enhanced p-IκBα and p-ERK activation and the nuclear translocation of RelA. Our study suggests that the protective function of PAE is mediated via enhanced NF-κB and ERK signaling.

L-Tetrahydropalmatine Inhibits the Progression of Glioblastoma Tumor by Suppressing the Extracellular-Signal-Regulated Kinase/Nuclear Factor-Kappa B Signaling Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 164-171
Author(s):  
Feng Xue ◽  
Tingting Chen
Keyword(s):  
Glioblastoma Multiforme ◽  
Nuclear Factor Kappa B ◽  
Matrix Metalloproteinase 2 ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Extracellular Signal ◽  
Apoptosis Protein ◽  
Endothelial Growth Factor

Glioblastoma multiforme is the most common malignancy of central nervous system. Herein we have evaluated the effect of L-tetrahydropalmatine, an isoquinoline alkaloid, on the tumor growth both in vivo and in vitro using C6 glioblastoma multiforme cells and BALB/c mice injected subcutaneously with C6/luc2 cells. The results of these studies show that L-tetrahydropalmatine exhibited cytotoxic effect on C6 glioblastoma multiforme cells, suppressed nuclear factor-kappa B activity, suppressed the levels of tumor-linked proteins such as matrix metalloproteinase-2/9, Cyclin-D1, vascular endothelial growth factor, and X-linked inhibitor of apoptosis protein via ERK/nuclear factor-kappa B cascade. Further, L-tetrahydropalmatine inhibited the cell migration and invasion properties of C6 cells, and also suppressed the tumor weight and volume in mice. Immunohistochemical staining of tumor tissues suggested that L-tetrahydropalmatine inhibited the extracellular-signal-regulated kinase/nuclear factor-kappa B cascade and suppressed the levels of Cyclin-D1; matrix metalloproteinase-2/9; X-linked inhibitor of apoptosis protein; and vascular endothelial growth factor, and also the progression and growth of glioblastoma multiforme in mice. In summary, L-tetrahydropalmatine inhibits the ERK/nuclear factor-kappa B cascade, decreases the tumor volume, and inhibits the proteins responsible for tumor growth both in vivo and in vitro.

scholarly journals Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

2010 ◽  
Vol 23 (3) ◽  
pp. 590-615 ◽  
Author(s):  
Soichiro Kanoh ◽  
Bruce K. Rubin
Keyword(s):  
Nuclear Factor Kappa B ◽  
Biological Activities ◽  
Mechanisms Of Action ◽  
Nuclear Factor ◽  
Diffuse Panbronchiolitis ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Regulation Of Cell Cycle ◽  
Immunomodulatory Therapies

SUMMARY Macrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-κB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.

scholarly journals Interferon α Induces Nucleus-independent Apoptosis by Activating Extracellular Signal-regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase Downstream of Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin

2008 ◽  
Vol 19 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Theocharis Panaretakis ◽  
Linn Hjortsberg ◽  
Katja Pokrovskaja Tamm ◽  
Ann-Charlotte Björklund ◽  
Bertrand Joseph ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Interferon Α ◽  
Dependent Manner ◽  
Phosphatidylinositol 3 Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Induced Apoptosis ◽  
Phosphatidylinositol 3

Interferon (IFN)α induces apoptosis via Bak and Bax and the mitochondrial pathway. Here, we investigated the role of known IFNα-induced signaling cascades upstream of Bak activation. By pharmacological and genetic inhibition of the kinases protein kinase C (PKC)δ, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) in U266-1984 and RHEK-1 cells, we could demonstrate that all three enzymes are critical for the apoptosis-associated mitochondrial events and apoptotic cell death induced by IFNα, at a step downstream of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Furthermore, the activation of JNK was found to occur in a PKCδ/ERK-dependent manner. Inhibition of these kinases did not affect the canonical IFNα-stimulated Janus tyrosine kinase-signal transducer and activator of transcription signaling or expression of IFN-responsive genes. Therefore, enucleated cells (cytoplasts) were examined for IFNα-induced apoptosis, to test directly whether this process depends on gene transcription. Cytoplasts were found to undergo apoptosis after IFNα treatment, as analyzed by several apoptosis markers by using flow cytometry, live cell imaging, and biochemical analysis of flow-sorted cytoplasts. Furthermore, inhibition of mTOR, ERK, and JNK blocked IFNα-induced apoptosis in cytoplasts. In conclusion, IFNα-induced apoptosis requires activation of ERK1/2, PKCδ, and JNK downstream of PI3K and mTOR, and it can occur in a nucleus-independent manner, thus demonstrating for the first time that IFNα induces apoptosis in the absence of de novo transcription.

scholarly journals 4-Hydroxy-7-Methoxycoumarin Inhibits Inflammation in LPS-activated RAW264.7 Macrophages by Suppressing NF-κB and MAPK Activation

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4424
Author(s):  
Jin Kyu Kang ◽  
Chang-Gu Hyun
Keyword(s):  
Nitric Oxide ◽  
Nuclear Factor Kappa B ◽  
Inflammatory Diseases ◽  
Raw264.7 Cells ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Alternative Medicines ◽  
Raw264.7 Macrophages ◽  
Extracellular Signal ◽  
Anti Inflammatory

Coumarins are natural products with promising pharmacological activities owing to their anti-inflammatory, antioxidant, antiviral, anti-diabetic, and antimicrobial effects. Coumarins are present in many plants and microorganisms and have been widely used as complementary and alternative medicines. To date, the pharmacological efficacy of 4-hydroxy-7-methoxycoumarin (4H-7MTC) has not been reported yet. Therefore, in this study, we investigated the anti-inflammatory effects of 4H-7MTC in LPS-stimulated RAW264.7 cells as well as its mechanisms of action. Cells were treated with various concentrations of 4H-7MTC (0.3, 0.6, 0.9, and 1.2 mM) and 40 μM L-N6-(1-iminoethyl)-L-lysine (L-NIL) were used as controls. LPS-stimulated RAW264.7 cells showed that 4H-7MTC significantly reduced nitric oxide (NO) and prostaglandin E2 (PGE2) production without cytotoxic effects. In addition, 4H-7MTC strongly decreased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Furthermore, 4H-7MTC reduced the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. We also found that 4H-7MTC strongly exerted its anti-inflammatory actions by downregulating nuclear factor kappa B (NF-κB) activation by suppressing inhibitor of nuclear factor kappa B alpha (IκBα) degradation in macrophages. Moreover, 4H-7MTC decreased phosphorylation of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase/stress-activated protein kinase (JNK), but not that of p38 MAPK. These results suggest that 4H-7MTC may be a good candidate for the treatment or prevention of inflammatory diseases such as dermatitis, psoriasis, and arthritis. Ultimately, this is the first report describing the effective anti-inflammatory activity of 4H-7MTC.

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