Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin and insulin analogs stimulate proliferation of human mammary epithelial cells. We identified and analyzed the signaling pathways related to cell proliferation induced by regular insulin and by four insulin analogs presently approved for therapeutical use. Benign and malignant mammary cell lines showing different insulin receptor (IR) and IGF-I receptor (IGF-IR) expression patterns were studied. Cell proliferation was studied by crystal violet staining (BrdU-FACS analysis). Activation of insulin and IGF signaling pathways was studied by analysis of the phosphorylation status of IGF-IR and of key signaling proteins of the phosphoinositide 3-kinase (PI3K)/Akt and MAP kinase pathways, by the use of specific PI3K and MAP kinase inhibitors, and by silencing of IR and IGF-IR. Lantus stimulated the growth of MCF7 cells, which show high IGF-IR/IR ratio, significantly at 0.3 nmol/l, while regular insulin (Actrapid and bovine insulin) and other insulin analogs (Novorapid, Humalog, and Levemir) stimulated cell growth at 1.5-15 nmol/l concentrations. No difference between Lantus and the other insulin analogs was observed regarding growth stimulation of MCF10A cells showing low IGF-IR/IR ratio. Growth stimulation of MCF7 cells by Lantus was mainly due to strong activation of the IGF-IR and the MAP kinase pathway. Regular insulin and other insulin analogs tested activated mainly the IR and the PI3K/Akt pathway. We conclude that unlike regular insulin and other insulin analogs, Lantus strongly activates the IGF-IR and the MAP kinase pathway in MCF7 cells and is a strong mitogen for cells characterized by a high-IGF-IR/IR ratio.
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PMID:Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines. 1915 8

Skin reactions at the infusion site are a common side effect of continuous subcutaneous insulin infusion therapy. We hypothesized that local skin complications are caused by components of commercial insulin formulations that contain phenol or m-cresol as excipients. The toxic potential of insulin solutions and the mechanisms leading to skin reactions were explored in cultured cells. The toxicity of insulin formulations (Apidra, Humalog, NovoRapid, Insuman), excipient-free insulin, phenol and m-cresol was investigated in L929 cells, human adipocytes and monocytic THP-1 cells. The cells were incubated with the test compounds dose- and time-dependently. Cell viability, kinase signaling pathways, monocyte activation and the release of pro-inflammatory cytokines were analyzed. Insulin formulations were cytotoxic in all cell-types and the pure excipients phenol and m-cresol were toxic to the same extent. P38 and JNK signaling pathways were activated by phenolic compounds, whereas AKT phosphorylation was attenuated. THP-1 cells incubated with sub-toxic levels of the test compounds showed increased expression of the activation markers CD54, CD11b and CD14 and secreted the chemokine MCP-1 indicating a pro-inflammatory response. Insulin solutions displayed cytotoxic and pro-inflammatory potential caused by phenol or m-cresol. We speculate that during insulin pump therapy phenol and m-cresol might induce cell death and inflammatory reactions at the infusion site in vivo. Inflammation is perpetuated by release of MCP-1 by activated monocytic cells leading to enhanced recruitment of inflammatory cells. To minimize acute skin complications caused by phenol/m-cresol accumulation, a frequent change of infusion sets and rotation of the infusion site is recommended.
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PMID:Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release. 2896 51