Metabolism-dependent stimulation of reactive oxygen species and DNA synthesis by cyclosporin A in rat smooth muscle cells

Nguyen, Nathalie S D; Cottet-Maire, Florence; Buetler, Timo M.; Russo, A; Krauskopf, Alexandra; Armstrong, J. M.; Vickers, Alison E. M.; Macé, Katherine; Rüegg, Urs T.

doi:10.1016/s0891-5849(99)00160-4

Cited by 24 publications

(13 citation statements)

References 47 publications

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“…It should also be noted that despite its well-recognized use and efficacy as an inhibitor of calcineurin, cyclosporin A may produce nonspecific side effects via the stimulation of superoxide (32). However, at least two studies have suggested that this side effect is associated with an increase in cell proliferation and DNA synthesis (43,66), the opposite of the data presented herein.…”

Section: Discussioncontrasting

confidence: 55%

MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation

Riddle

Taylor

Genetos

et al. 2006

American Journal of Physiology-Cell Physiology

172

136

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Although the mechanisms by which osteoblasts and osteocytes respond to fluid flow are being elucidated, little is known about the mechanisms by which bone marrow-derived mesenchymal stem cells respond to such stimuli. Here we show that the intracellular signaling cascades activated in human mesenchymal stem cells by fluid flow are similar to those activated in osteoblastic cells. Oscillatory fluid flow inducing shear stresses of 5, 10, and 20 dyn/cm 2 triggered rapid, flow rate-dependent increases in intracellular calcium that pharmacological studies suggest are inositol trisphosphate mediated. The application of fluid flow also induced the phosphorylation of extracellular signal-regulated kinase-1 and -2 as well as the activation of the calcium-sensitive protein phosphatase calcineurin in mesenchymal stem cells. Activation of these signaling pathways combined to induce a robust increase in cellular proliferation. These data suggest that mechanically induced fluid flow regulates not only osteoblastic behavior but also that of mesenchymal precursors, implying that the observed osteogenic response to mechanical loading may be mediated by alterations in the cellular behavior of multiple members of the osteoblast lineage, perhaps by a common signaling pathway. mechanotransduction; bone; marrow MAINTENANCE OF APPROPRIATE bone mass requires the coordination of bone resorption by osteoclasts and bone deposition by osteoblasts, and it is well established that mechanical stimuli can regulate the balance between bone formation and resorption. The addition of exogenous mechanical load is believed to stimulate new bone formation through increases in osteoblastic activity and concomitant decreases in osteoclastic activity (20). Conversely, removal of mechanical load, as is the case during spaceflight and disuse, leads to decreased osteoblastic activity and loss of bone mass (42,56).Accumulating evidence suggests that individual bone cells, including osteocytes and osteoblasts, are responsible for perceiving and responding to mechanical signals. Such signals, which may include streaming potentials, mechanical strain, and fluid shear stress, elicit a host of biochemical responses including mobilization of second messengers such as calcium (22,72), nitric oxide (26, 30), prostaglandins, and inositol trisphosphate (IP 3 ) (49); activation of kinase cascades including the MAP kinase and PKC pathways (44, 50); and modulation of gene expression (5, 46, 73). Strain-induced oscillatory fluid flow has been shown by our laboratory (73) and others (45) to be a potent biophysical stimulus. In MC3T3-E1 preosteoblasts, fluid flow induces the mobilization of intracellular calcium (Ca i 2ϩ ), activates ERK1/2, and increases osteopontin mRNA levels (11,72,73). Recent evidence has shown that exposing the osteocytic cell line MLO-Y4 to physiological levels of fluid flow induces similar responses (1, 6, 52).Although the mechanisms by which osteoblasts and osteocytes respond to mechanical stimuli are being elucidated, little is known about how bo...

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Section: Discussioncontrasting

confidence: 55%

MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation

Riddle

Taylor

Genetos

et al. 2006

American Journal of Physiology-Cell Physiology

172

136

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“…While the time kinetics experiments support the role of mitochondria as a source of ROS, we were not able to directly prove this assumption, as mitochondrial hyperpolarization by CsA was somewhat paradoxically associated with a dramatic increase in intracellular ROS levels. This presumably mitochondriaindependent effect could be due to excessive superoxide and/or H 2 O 2 formation during intracellular metabolism of CsA [27].…”

Section: Discussionmentioning

confidence: 99%

Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis

Isaković

Harhaji²,

Stevanović

et al. 2007

Cell. Mol. Life Sci.

184

158

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The present study reports for the first time a dual antiglioma effect of the well-known antidiabetic drug metformin. In low-density cultures of the C6 rat glioma cell line, metformin blocked the cell cycle progression in G(0)/G(1) phase without inducing significant cell death. In confluent C6 cultures, on the other hand, metformin caused massive induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation, mitochondrial depolarization and oxidative stress. Metformin-triggered apoptosis was completely prevented by agents that block mitochondrial permeability transition (cyclosporin A) and oxygen radical production (N-acetylcisteine), while the inhibitors of JNK activation (SP600125) or glycolysis (sodium fluoride, iodoacetate) provided partial protection. The antiglioma effect of metformin was reduced by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and was mimicked by the AMPK agonist AICAR. Similar effects were observed in the human glioma cell line U251, while rat primary astrocytes were completely resistant to the antiproliferative and proapoptotic action of metformin.

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“…CsA is known to generate free radicals in microsomes isolated from rat and human liver, and increase MDA production in a dose-dependent fashion [14,15]. CsA was found to generate rapid (within 10 min) reactive oxygen species in rat smooth muscle cells [16]. In in vivo animal studies, CsA induced rat kidney failure and increased the glomerular synthesis of superoxide anion, H 2 O 2 , MDA, and thromboxane B2.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A-Induced Lipid and Protein Oxidation in Human B-Cells and in Epstein-Barr Virus-Infected B-Cells is Prevented by Antioxidants

Chen

Jeon

Johnston

et al. 2008

Journal of Investigative Surgery

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The incidence of post-transplant lymphoproliferative disorder (PTLD) has increased since cyclosporin A (CsA) became the mainstay of transplant immunosuppression. We have previously shown that, in addition to its potent immunosuppressive property, CsA-induced oxidative stress plays an important role in Epstein-Barr virus (EBV)-related PTLD. Using lipid hydroperoxide and malondialdehyde as markers of lipid oxidation, and protein carbonyls as markers of protein oxidation, we further investigated the in vitro effect of CsA on human B cells and EBV-infected human B cells. We found that CsA at 500 ng/ml, a relatively safe and effective blood concentration in organ transplant recipients, induced the highest lipid hydroperoxide and malondialdehyde after 10 min of treatment in time- and concentration-related kinetic studies. We also found that treatment with CsA at 500 ng/ml for 10 min increased the EBV-infected B cell protein carbonyl formation as assayed by immunoblot method. CsA-induced lipid and protein oxidation could be inhibited by vitamin E, N-acetyl cysteine, and pyrollidine dithiocarbamate. CsA significantly promoted the EBV-B cell transformation as assayed by colony counting, cell counting, and (3)H-thymidine incorporation. Our recent study provides further evidence to support the hypothesis that CsA exerts direct oxidative stress in EBV-infected as well as non-EBV-infected human B cells. A greater understanding of these cellular and molecular mechanisms may benefit the clinical practice and prevention of PTLD.

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Metabolism-dependent stimulation of reactive oxygen species and DNA synthesis by cyclosporin A in rat smooth muscle cells

Cited by 24 publications

References 47 publications

MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation

MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation

Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis

Cyclosporin A-Induced Lipid and Protein Oxidation in Human B-Cells and in Epstein-Barr Virus-Infected B-Cells is Prevented by Antioxidants

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