AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells.

The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the alpha subunit of AMPK in a dose- and time-dependent manner.

Temporal control of NF-kappaB activation by ERK differentially regulates interleukin-1beta-induced gene expression.

In cultured rat vascular smooth muscle cells, sustained activation of ERK is required for interleukin-1beta to persistently activate NF-kappaB. Without ERK activation, interleukin-1beta induces only acute and transient NF-kappaB activation. The present study examined whether the temporal control of NF-kappaB activation by ERK could differentially regulate the expression of NF-kappaB-dependent genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1), and manganese-containing superoxide dismutase (Mn-SOD).

Growth factors enhance interleukin-1 beta-induced persistent activation of nuclear factor-kappa B in rat vascular smooth muscle cells.

Objective: Activation of extracellular signal-regulated kinases (ERKs) is required for interleukin-1beta to persistently activate nuclear factor (NF)-kappaB and concomitantly express inducible NO synthase (iNOS) in rat vascular smooth muscle cells (VSMCs). The present study examined whether platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) could influence the VSMC response to interleukin-1beta via an ERK-related signaling pathway.

Methods And Results: Treatment of VSMCs with PDGF or EGF alone potently induced ERK phosphorylation and DNA synthesis but did not induce NF-kappaB activation or iNOS expression.

Selective inhibition of STAT3 phosphorylation by sodium salicylate in cardiac fibroblasts.

The effects of salicylate on the phosphorylation and nuclear translocation of signal transducers and activators of transcription (STATs) induced by interferon-gamma (IFN-gamma) were studied in rat cardiac fibroblasts as a possible model for the anti-inflammatory effects of salicylate on this signaling pathway. Salicylate inhibited the tyrosine phosphorylation of both STAT1 and STAT3, but had a more pronounced effect on STAT3 activation. Salicylate pretreatment prevented both the nuclear translocation and the DNA-binding activity of STAT1 and STAT3, assessed by immunoblotting and gel shift assays, respectively.

Persistent activation of nuclear factor-kappaB by interleukin-1beta and subsequent inducible NO synthase expression requires extracellular signal-regulated kinase.

The role of extracellular signal-regulated kinase (ERK) was studied in the signaling pathway by which interleukin-1beta (IL-1beta) increases the expression of inducible NO synthase (iNOS) in rat vascular smooth muscle cells. IL-1beta induced a rapid and transient activation of nuclear factor-kappaB (NF-kappaB), followed by a prolonged activation of NF-kappaB that was required to induce iNOS expression. Either PD98059 or U0126, selective inhibitors of ERK activation, did not influence IL-1beta-induced early activation but effectively reduced the prolonged activation of NF-kappaB and significantly reduced IL-1beta induction of iNOS.