Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a ligand-activated transcription factor important in lipid metabolism, diabetes, and inflammation. We evaluated whether human platelets and megakaryocytes express PPAR␥ and whether PPAR␥ agonists influence platelet release of bioactive mediators. Although PPAR␥ is mainly considered a nuclear receptor, we show that enucleate platelets highly express PPAR␥ protein as shown by Western blotting, flow cytometry, and immunocytochemistry. Meg-01 megakaryocyte cells and human bone marrow megakaryocytes also express PPAR␥. Platelet and Meg-01 PPAR␥ bound the PPAR␥ DNA consensus sequence, and this was enhanced by PPAR␥ agonists. Platelets are essential not only for clotting, but have an emerging role in inflammation in part due to their release or production of the proinflammatory and proatherogenic mediators CD40 ligand (CD40L) and thromboxanes (TXs). Platelet incubation with a natural PPAR␥ agonist, 15d-PGJ 2 , or with a potent synthetic PPAR␥ ligand, rosiglitazone, prevented thrombin-induced CD40L surface expression and release of CD40L and thromboxane B 2 (TXB 2 ). 15d-PGJ 2 also inhibited platelet aggregation and adenosine triphosphate ( IntroductionPeroxisome proliferator-activated receptors (PPARs) are members of a nuclear hormone receptor superfamily of ligandactivated transcription factors. There are 3 PPAR subtypes: PPAR␣, PPAR␤/␦, and PPAR␥. The genes encoding the PPAR subtypes each reside on different chromosomes and have distinct tissue expression patterns. 1 While many reports focus on PPAR expression in the nucleus, PPAR␥, in particular, is also found in the cytoplasm. 2,3 PPAR␥ is highly expressed in white adipose tissue and was initially described as important for regulating gene expression in metabolism, insulin responsiveness, and adipocyte differentiation. 4,5 While PPAR␥ was originally thought to be found mainly in fat tissue, it is in fact widely expressed by many types of cells including macrophages, B and T lymphocytes, epithelial, endothelial, smooth muscle, and fibroblastic cells. 2,[6][7][8][9][10][11] PPAR␥ has also come to prominence as PPAR␥ agonists play an important role in immune function by dampening inflammation, attenuating macrophage/monocyte synthesis of proinflammatory cytokines, and inducing apoptosis in B lymphocytes. 2,6,12,13 PPAR␥ has also emerged as a key target for malignant cells as PPAR␥ agonists have shown therapeutic potential for B lymphoma and various epithelialderived cancers. 2,14,15 Megakaryocytes are the biggest cell of the bone marrow and the parent cell of platelets. Platelets are derived from the cytoplasm of megakaryocytes and are released to the bloodstream under the effects of cytokines such as interleukin-6 (IL-6) and 17 Platelets are enuclear cells that have a plasma membrane, surface-connected canalicular and tubular system, mitochondria, granules, lysosomes, and peroxisomes. 18 Recent studies demonstrate that platelets and many of their products are important not only in hemostasis, but have now emerg...

Lipid peroxidation has been reported to play an important role in spinal cord injury (SCI). Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system. The purpose of this study was to investigate the effectiveness of recombinant human EPO in attenuating the severity of experimental SCI. Rats were divided into seven groups. Controls (1) received only laminectomy. The trauma-only group (2) underwent 50-g/cm contusion injury and had no medication. In group 3, 30 mg/kg of methylprednisolone was introduced. The vehicle group (4) received vehicle solution containing human serum albumin, which is a solvent of EPO. Groups 5, 6, and 7 received 100 IU/kg, 1,000 IU/kg, and 5,000 IU/kg of EPO, respectively. All treatments were given as single doses, intraperitoneally, immediately after injury. Thiobarbituric acid-reactive substances were estimated to demonstrate lipid peroxidation, and ultrastructure was evaluated by electron microscopy. The results showed that lipid peroxidation by-products increased after injury. Administration of EPO and methylprednisolone sodium succinate (MPSS) reduced thiobarbituric acid-reactive substances after trauma. The best biochemical results were obtained with 5,000 IU/kg of EPO. Electron microscopic findings showed that EPO protected the spinal cord from injury. Although 1,000 IU/kg and 5,000 IU/kg of EPO inhibited lipid peroxidation better than MPSS, ultrastructural neuroprotection was similar.

Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor important for adipogenesis and more recently has been shown to be an anticancer target. PPARγ ligands, including the endogenous ligand 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) and synthetic ligands like ciglitazone and troglitazone, all induce apoptosis in normal and malignant human B lymphocytes, but the dependency of PPARγ for apoptosis induction is unknown. In this study, we used a PPARγ dominant-negative approach and a small molecule irreversible PPARγ antagonist and found that these inhibitors prevented PPARγ activation but did not prevent B cell apoptosis induced by 15d-PGJ2 or ciglitazone. In addition, a PPARγ agonist that is a structural analog of 15d-PGJ2, and lacks the electrophilic carbon of the 15d-PGJ2 cyclopentenone ring, activated PPARγ but did not kill B lymphocytes, further supporting a non-PPARγ-mediated mechanism. To further investigate the apoptotic mechanism, the effects of 15d-PGJ2 and ciglitazone on reactive oxygen species were investigated. 15d-PGJ2, but not ciglitazone, potently induced reactive oxygen species in B lymphocytes, implicating the reactive nature of the 15d-PGJ2 structure in the apoptosis mechanism. In addition, 15d-PGJ2 caused an almost complete depletion of intracellular glutathione. Moreover, incubation with glutathione reduced ethyl ester, an antioxidant, prevented apoptosis induced by 15d-PGJ2, but not by ciglitazone. These findings indicate that the expression of PPARγ may not be predictive of whether a normal or malignant B lineage cell is sensitive to PPARγ agonists. Furthermore, these new findings support continued investigation into the use of PPARγ agonists as agents to attenuate normal B cell responses and as anti-B cell lymphoma agents.