Fucoidan Inhibits Smooth Muscle Cell Proliferation and Reduces Mitogen-activated Protein Kinase Activity

AbstractObjectives and design: fucoidan has previously been shown to inhibit the proliferation of arterial smooth muscle cells both in animal models and in vitro. However, the mechanisms behind the anti-proliferative effects of this polysulfated polysaccharide are not known in detail. Here, the inhibitory effect of fucoidan on rat aortic smooth muscle cell proliferation was examined and compared with the effects of heparin after stimulation with fetal calf serum, platelet-derived growth factor BB, basic fibroblast growth factor, heparin-binding epidermal growth factor, and angiotensin II. Materials and methods: the cultures were analysed with respect to cell proliferation and DNA synthesis by cell counting and measurement of3H-thymidine incorporation. Phosphorylation of mitogen-activated protein kinase and nuclear translocation of phosphorylated mitogen-activated protein kinase were studied by immunoblotting and immunocytochemistry. Results: fucoidan was shown to be a more potent inhibitor of smooth muscle cell proliferation than heparin. Fucoidan also reduced growth factor-induced activation of mitogen-activated protein kinase and prevented nuclear translocation of phosphorylated mitogen-activated protein kinase. Conclusion: fucoidan is a more potent anti-proliferative polysulphated polysaccharide than heparin and may mediate its effects through inhibition of the mitogen-activated protein kinase pathway in a similar manner as heparin

Total ginsenosides suppress monocrotaline-induced pulmonary hypertension in rats: involvement of nitric oxide and mitogen-activated protein kinase pathways

AbstractBackgroundGinsenosides have been shown to exert beneficial pharmacological effects on the central nervous, cardiovascular, and endocrine systems. We sought to determine whether total ginsenosides (TG) inhibit monocrotaline (MCT)-induced pulmonary hypertension and to elucidate the underlying mechanism.MethodsMCT-intoxicated rats were treated with gradient doses of TG, with or without NG-nitro-l-arginine methyl ester. The levels of molecules involving the regulation of nitric oxide and mitogen-activated protein kinase pathways were determined.ResultsTG ameliorated MCT-induced pulmonary hypertension in a dose-dependent manner, as assessed by the right ventricular systolic pressure, the right ventricular hypertrophy index, and pulmonary arterial remodeling. Furthermore, TG increased the levels of pulmonary nitric oxide, endothelial nitric oxide synthase, and cyclic guanosine monophosphate. Lastly, TG increased mitogen-activated protein kinase phosphatase-1 expression and promoted the dephosphorylation of extracellular signal-regulated protein kinases 1/2, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase 1/2.ConclusionTG attenuates MCT-induced pulmonary hypertension, which may involve in part the regulation of nitric oxide and mitogen-activated protein kinase pathways

Kinase Activity Profiling of Gram-Negative Pneumonia

Pneumonia is a severe disease with high morbidity and mortality. A major causative pathogen is the Gram-negative bacterium Klebsiella (K.) pneumoniae. Kinases play an integral role in the transduction of intracellular signaling cascades and regulate a diverse array of biological processes essential to immune cells. The current study explored signal transduction events during murine Gram-negative pneumonia using a systems biology approach. Kinase activity arrays enable the analysis of 1,024 consensus sequences of protein kinase substrates. Using a kinase activity array on whole lung lysates, cellular kinase activities were determined in a mouse model of K. pneumoniae pneumonia. Notable kinase activities also were validated with phospho-specific Western blots. On the basis of the profiling data, mitogen-activated protein kinase (MAPK) signaling via p42 mitogen-activated protein kinase (p42) and p38 mitogen-activated protein kinase (p38) and transforming growth factor β (TGFβ) activity were reduced during infection, whereas v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) activity generally was enhanced. AKT signaling was represented in both metabolic and inflammatory (mitogen-activated protein kinase kinase 2 [MKK], apoptosis signal-regulating kinase/mitogen-activated protein kinase kinase kinase 5 [ASK] and v-raf murine sarcoma viral oncogene homolog B1 [b-RAF]) context. This study reaffirms the importance of classic inflammation pathways, such as MAPK and TGFβ signaling and reveals less known involvement of glycogen synthase kinase 3β (GSK-3β), AKT and SRC signaling cassettes in pneumonia

Antioxidant and anti-inflammatory effects in RAW264.7 macrophages of malvidin, a major red wine polyphenol.

Background Red wine polyphenols can prevent cardiovascular and inflammatory diseases. Resveratrol, the most extensively studied constituent, is unlikely to solely account for these beneficial effects because of its rather low abundance and bioavailability. Malvidin is far the most abundant polyphenol in red wine; however, very limited data are available about its effect on inflammatory processes and kinase signaling pathways. METHODS FINDINGS: The present study was carried out by using RAW 264.7 macrophages stimulated by bacterial lipopolysaccharide in the presence and absence of malvidin. From the cells, activation of nuclear factor-kappaB, mitogen-activated protein kinase, protein kinase B/Akt and poly ADP-ribose polymerase, reactive oxygen species production, mitogen-activated protein kinase phosphatase-1 expression and mitochondrial depolarization were determined. We found that malvidin attenuated lipopolysaccharide-induced nuclear factor-kappaB, poly ADP-ribose polymerase and mitogen-activated protein kinase activation, reactive oxygen species production and mitochondrial depolarization, while upregulated the compensatory processes; mitogen-activated protein kinase phosphatase-1 expression and Akt activation. CONCLUSIONS These effects of malvidin may explain the previous findings and at least partially account for the positive effects of moderate red wine consumption on inflammation-mediated chronic maladies such as obesity, diabetes, hypertension and cardiovascular disease

Myocardial depressant effects of interleukin 6 in meningococcal sepsis are regulated by p38 mitogen-activated protein kinase

Our findings demonstrate an integral role of the p38 mitogen-activated protein kinase pathway in interleukin 6-mediated cardiac contractile dysfunction and inotrope insensitivity. Dysregulation of the p38 mitogen-activated protein kinase pathway in meningococcal septicemia suggests that this pathway may be an important target for novel therapies to reverse myocardial dysfunction in patients with meningococcal septic shock who are not responsive to inotropic support

Mitogen-activated protein kinases mediate Mycobacterium tuberculosis–induced CD44 surface expression in monocytes

CD44, an adhesion molecule, has been reported to be a binding site for Mycobacterium tuberculosis (M. tuberculosis) in macrophages and it also mediates mycobacterial phagocytosis, macrophage recruitment and protective immunity against pulmonary tuberculosis in vivo. However, the signalling pathways that are involved in M. tuberculosis–induced CD44 surface expression in monocytic cells are currently unknown. Exposure of THP-1 human monocytes to M. tuberculosis H37Rv and H37Ra induced distinct, time-dependent, phosphorylation of mitogen-activated protein kinase kinase-1, extracellular signal regulated kinase 1/2, mitogen-activated protein kinase kinase 3/6, p38 mitogen-activated protein kinase and c-jun N-terminal kinases. The strains also differed in their usage of CD14 and human leukocyte antigen-DR (HLA-DR) receptors in mediating mitogen-activated protein kinase activation. M. tuberculosis H37Rv strain induced lower CD44 surface expression and tumour necrosis factor-alpha levels, whereas H37Ra the reverse. Using highly specific inhibitors of mitogen-activated protein kinase kinase-1, p38 mitogen-activated protein kinase and c-jun N-terminal kinase, we report that inhibition of extracellular signal regulated kinase 1/2 and c-jun N-terminal kinases increases, but that inhibition of p38 mitogen-activated protein kinase decreases M. tuberculosis–induced CD44 surface expression in THP-1 human monocytes

Correlation of P38 Mitogen-Activated Protein Kinase Expression to Clinical Stage in Nasopharyngeal Carcinoma

BACKGROUND: Nasopharyngeal carcinoma (NPC) is uncommon and usually diagnosed at the advanced stage. A subfamily of mitogen-activated protein kinase which is called p38 mitogen-activated protein kinase (MAPK) involved in response to stress, and plays an important role in cell regulation. There is a suggestion that p38 mitogen-activated protein kinase could be a potential biomarker to determine the clinical stage of nasopharyngeal carcinoma. AIM: The aim of this study is for observing and analysing the correlation of p38 mitogen-activated protein kinase expression in regards to nasopharyngeal carcinoma patient’s clinical stage. METHODS: This study involved 126 nasopharyngeal carcinoma patients admitted to Haji Adam Malik General Hospital. RESULTS: The result of this study indicates that nasopharyngeal carcinoma mostly found in the age group 41-60 years, male, non-keratinizing squamous cell carcinoma, and stage IV group. In immunohistochemistry evaluation, most of p38 mitogen-activated protein kinase overexpressed in non-keratinizing squamous cell carcinoma, T3-T4, N2-N3 and clinical stage III-IV. Spearman’s test for categorical correlation yield p-value of < 0.001. CONCLUSION: In conclusion, there is a significant correlation between p38 mitogen-activated protein kinase expression and the clinical stage of nasopharyngeal carcinoma

Precision medicine driven by cancer systems biology

Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance

Targeting MAPK in Cancer 2.0

Mitogen-activated protein kinase (MAPK) pathways are prominently involved in the onset and progression of cancer [...

Sequence patches on MAPK surfaces define protein-protein interactions

Redesigning ‘surface patches’ on a mitogen-activated protein kinase can change its interactions with other proteins