Imatinib protects against human beta-cell death via inhibition of mitochondrial respiration and activation of AMPK.

The protein tyrosine kinase inhibitor imatinib is used in the treatment of various malignancies but may also promote beneficial effects in the treatment of diabetes. The aim of the present investigation was to characterize the mechanisms by which imatinib protects insulin producing cells. Treatment of non-obese diabetic (NOD) mice with imatinib resulted in increased beta-cell AMP-activated kinase (AMPK) phosphorylation.

The protein synthesis inhibitor brusatol normalizes high-fat diet-induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination.

The naturally occurring quassinoid compound brusatol improves the survival of insulin-producing cells when exposed to the proinflammatory cytokines IL-1β and IFN-γ in vitro. The aim of the present study was to investigate whether brusatol also promotes beneficial effects in mice fed a high-fat diet (HFD), and if so, to study the mechanisms by which brusatol acts. In vivo, we observed that the impaired glucose tolerance of HFD-fed male C57BL/6 mice was counteracted by a 2 wk treatment with brusatol.

Aromatic malononitriles stimulate the resistance of insulin-producing beta-cells to oxidants and inflammatory cytokines.

We presently report that treatment with tyrphostin AG-126 (2-(3-hydroxy-4-nitrobenzylidene)malononitrile) and ten other aromatic malononitrile compounds (AMN) improves the resistance of insulin-producing βTC6, RIN-5AH, and MIN6 cells to oxidative stress and pro-inflammatory cytokines. On the molecular level AMN compounds promote nuclear accumulation of the Nrf2 transcription factor and expression of the cytoprotective genes heme ogygenase 1 (HO-1) and NAD(P)H/quinone oxidoreductase 1 (NQO1), inhibit cytokine-dependent inducible nitric oxide synthase (iNOS) induction, suppress intracellular production of reactive oxygen species in βTC6 and counteract to impairments of glucose-stimulated insulin secretion induced by pro-inflammatory cytokines in MIN6 cells. Nrf2 up-regulation and HO-1 induction by AG-126 are attenuated at the presence of siRNA against Nrf2 and brusatol, an inhibitor of the Nrf2 signaling pathway.

Brusatol inhibits the response of cultured beta-cells to pro-inflammatory cytokines in vitro.

Brusatol is a natural terpenoid that is capable of inducing a variety of biological effects. We presently report that this substance dramatically improves beta-cell survival when exposed to pro-inflammatory cytokines (IL-1β and IFNγ) in vitro. This was observed in insulin producing rat (RIN-5AH), mouse (βTC6) and human (EndoC-βH1) beta-cell lines.

Co-culture of neural crest stem cells (NCSC) and insulin producing beta-TC6 cells results in cadherin junctions and protection against cytokine-induced beta-cell death.

Purpose: Transplantation of pancreatic islets to Type 1 diabetes patients is hampered by inflammatory reactions at the transplantation site leading to dysfunction and death of insulin producing beta-cells. Recently we have shown that co-transplantation of neural crest stem cells (NCSCs) together with the islet cells improves transplantation outcome. The aim of the present investigation was to describe in vitro interactions between NCSCs and insulin producing beta-TC6 cells that may mediate protection against cytokine-induced beta-cell death.

Benzylidenemalononitrile compounds as activators of cell resistance to oxidative stress and modulators of multiple signaling pathways. A structure-activity relationship study.

Benzylidenemalononitrile (BMN) tyrphostins are well known as potent tyrosine kinase inhibitors. Moreover, in recent years it has been recognized that members of the tyrphostin family possess additional biological activities independent of their ability to inhibit protein tyrosine kinases. In this study, we examined the relationship between the structure of 49 BMNs and related compounds, and their capacity to induce heme oxygenase 1 (HO-1) gene expression in U937 human monocytic cells, to activate upstream signaling pathways and to protect cells against menadione-induced oxidative stress.

Variation in gene expression profiles of human monocytic U937 cells exposed to various fluxes of nitric oxide.

We examined early and late alterations in gene expression patterns and phosphorylation levels of key regulators of selected signaling pathways in U937 cells exposed to various (*)NO fluxes. cDNA microarray analysis and real-time quantitative PCR identified 45 NO-sensitive genes (>or=2-fold change), among which KLF2, KLF6, TSC22D3, DDIT4, MKP-5 (up-regulated), KIF23, histone H4, ARL6IP2, CLNS1A, SLC7A6, CDKN3, SRP19, and BCL11A (down-regulated) have not been reported before. For two selected genes, KLF2 and DDIT4, the sensitivity to (.

Stimulatory effect of benzylidenemalononitrile tyrphostins on expression of NO-dependent genes in U-937 monocytic cells.

Tyrphostins are well-established selective inhibitors of protein tyrosine kinase activity of EGF receptor and other growth factor receptors. Unexpectedly, we found that, in U-937 monocytic cells, tyrphostin AG-126 augments the sensitivity of the corresponding genes to NO, in contrast to other protein tyrosine kinase inhibitors like genistein, PD 168393, PP2, and SU 11652. Moreover, by itself AG-126 appeared to be a potent activator of the expression of heme oxygenase 1 (HO-1), H-ferritin, activating transcription factor 3 (ATF3), interleukin 8 (IL-8), and several other NO- and redox-regulated genes.

Analysis of differentially expressed genes in nitric oxide-exposed human monocytic cells.

In this study we examined the gene expression pattern of *NO-dependent genes in U937 and Mono Mac 6 monocytes exposed to the synthetic NO-donor DPTA-NO using microarray technology. cDNA microarray data were validated by Northern blot analysis and quantitative real-time PCR. This approach allowed the identification of 17 *NO-sensitive genes that showed at least a twofold difference in expression, in both U937 cells and Mono Mac 6 cells exposed to 500 microM DPTA-NO for 4 h.

Extracellular catalase induces cyclooxygenase 2, interleukin 8, and stromelysin genes in primary human chondrocytes.

We investigated the expression of genes in response to exposure of primary human chondrocytes to extracellular catalase. The addition of catalase to culture medium caused a significant up-regulation of cyclooxygenase 2, interleukin 8, and stromelysin mRNA levels. Similar pattern of gene activation occurred in chondrocytes incubated with horseradish peroxidase.

Nitric oxide-derived nitrosating species and gene expression in human monocytic cells.

In living cells, NO signaling is mediated by NO-derived metabolites and is therefore dependent on the rate of formation of these so-called reactive nitrogen intermediates (RNIs). We have examined the effects of NO-oxidizing agents, the nitronyl nitroxide PTIO and its less hydrophobic analogue carboxy-PTIO (CPTIO), on the expression of NO-sensitive genes in monocytic U937 and Mono Mac 6 cells. We have observed that pretreatment of cells with PTIO boosted expression of IL-8 and heme oxygenase 1 (HOX) genes to a high level in cells treated with the NO donor DPTA-NO.

Redox modulation of NO-dependent induction of interleukin 8 gene in monocytic U937 cells.

We have examined the effects of various antioxidants and inhibitors of redox-sensitive signal transduction pathways on induction of interleukin 8 (IL-8) gene by NO in monocytic U937 cells. We have observed that nitrosoglutathione or another NO-generating compound spermine NONOate caused significant accumulation of IL-8 mRNA. Pretreatment of cells with pyrrolidine dithiocarbamate or with antioxidants, which scavenge hydroxyl radical, dimethyl sulfoxide (DMSO), or dimetylthiourea (DMTU) completely abrogated NO-dependent induction of IL-8 gene expression.