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Kithcart A.P.,Ohio State University | Cox G.M.,Ohio State University | Sielecki T.,Cytokine PharmaSciences | Short A.,Ohio State University | And 6 more authors.
FASEB Journal | Year: 2010

Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS) characterized by demyelination and axon loss. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has been shown to be elevated in the cerebrospinal fluid of patients during relapses. The purpose of this study was to evaluate a new small-molecule inhibitor of MIF and its ability to reduce the severity of an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We utilized 2 structurally related isoxazolines, which show in vitro inhibition of MIF tautomerase activity. We found that administration of an inhibitor of MIF to mice with established EAE immediately reduced the severity of clinical signs and expanded a population of regulatory T lymphocytes. We also noted that the inhibitor reduced relapses of disease in a relapsing/remitting model of EAE. An analysis of leukocyte migration into the brain revealed that administration of inhibitor reduced entry of these cells. No effects on inflammatory cytokine production or T-cell activation in the periphery were noted. From these studies, we conclude that a small-molecule inhibitor of MIF reduces the severity of EAE and prevents access of immune cells into the CNS, which could be of therapeutic relevance to MS. © FASEB.

Sanchez-Zamora Y.,Ohio State University | Sanchez-Zamora Y.,National Autonomous University of Mexico | Terrazas L.I.,Ohio State University | Terrazas L.I.,National Autonomous University of Mexico | And 13 more authors.
FASEB Journal | Year: 2010

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in the pathogenesis of a variety of autoimmune inflammatory diseases. Here, we investigated the role of MIF in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) using MIF-/- mice and a mouse model of streptozotocin (STZ)-induced NIDDM. Following single injection of STZ, MIF+/+ BALB/c mice showed a significant increase in blood glucose levels, developed polyuria, and succumbed to disease. In contrast, no such increase in blood glucose was observed in MIF-/- BALB/c mice treated with STZ. These mice produced significantly less inflammatory cytokines and resistin as compared with MIF+/+ mice and failed to develop clinical disease. Finally, oral administration of a small-molecule MIF antagonist, CPSI-1306, to outbred ICR mice following induction of NIDDM significantly lowered blood glucose levels in the majority of animals, which was also associated with a significant reduction in the levels of the proinflammatory cytokines IL-6 and TNF-α in the sera. Taken together, these results demonstrate that MIF is involved in the pathogenesis of NIDDM and is a therapeutic target to treat this disease. © FASEB.

Nagarajan P.,Ohio State University | Tober K.L.,Ohio State University | Riggenbach J.A.,Ohio State University | Kusewitt D.F.,Anderson University, South Carolina | And 5 more authors.
Molecular Cancer Research | Year: 2014

Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduceUVBlight-induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX (γ-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non-tumorbearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306-treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure. © 2014 American Association for Cancer Research.

Brennan M.C.,University of New Mexico | Pevzner L.,University of California at Irvine | Wing D.A.,University of California at Irvine | Powers B.L.,Cytokine PharmaSciences | Rayburn W.F.,University of New Mexico
American Journal of Perinatology | Year: 2011

We evaluate the likelihood of cesarean delivery and identify risks of retaining a sustained-release dinoprostone vaginal insert beyond 12 hours. In a secondary analysis of outcomes, data were collected during a large, randomized trial comparing different sustained-release prostaglandin vaginal inserts for labor induction. Outcomes were compared between cases in whom the dinoprostone insert was removed early (within 12 hours) or late (12 to 24 hours). A total of 431 subjects had the dinoprostone vaginal insert in place for 12 to 24 hours (n = 226, 52.4%) or within 12 hours (n = 205, 47.6%). Insert removal for labor complications was less frequent in the late group than in the early group (5.8% versus 21.5%; p ≤ 0.001). Abnormal uterine contractility patterns were less common in the late than early group (25.2% versus 37.6%; p = 0.03). Rates of cesarean delivery during the first hospitalization were similar for late and early groups (25.0% versus 29.2%; p = 0.33). Percentages of infants requiring immediate attention or intensive care were low and similar between groups. Sustained-release intravaginal dinoprostone left in place beyond 12 hours did not increase the risks of intrapartum complications, cesarean delivery, or immediate adverse neonatal events. © 2011 by Thieme Medical Publishers, Inc.

Choudhary S.,University of Connecticut Health Center | Hegde P.,University of Connecticut Health Center | Pruitt J.R.,West Chester University | Sielecki T.M.,Cytokine PharmaSciences | And 5 more authors.
Carcinogenesis | Year: 2013

Macrophage migratory inhibitory factor (MIF) is a proinflammatory cytokine shown to promote tumorigenesis. Using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model of bladder cancer, we previously showed that MIF knockout mice display decreased angiogenesis and invasion compared with wild-type. This study examines the role of MIF in bladder cancer via use of oral inhibitors of MIF. In vitro, high-grade bladder cancer cells were treated with recombinant human MIF +/- (rhMIF+/-) inhibitor. Measurements included cell counts, proliferation by 3H-thymidine incorporation (TdR), extracellular signal-regulated kinase (ERK) phosphorylation by western blot analysis, messenger RNA (mRNA) expression by quantitative PCR and protein secretion by enzyme-linked immunosorbent assay. Treatment with rhMIF increased ERK phosphorylation, cell counts, TdR and mRNA expression and protein secretion of vascular endothelial growth factor, which were blocked by specific inhibitors of ERK and MIF. In vivo, 3-month-old male C57Bl/6 mice were given BBN for 22 and 16 weeks in study 1 and study 2, respectively. Mice (n = 8-10 per group) were gavaged with vehicle or doses of MIF inhibitors daily from weeks 16-22 in both studies. Average bladder weights, reflecting tumor mass, tumor stage/ burden, mitotic rate and proliferation indices, and microvessel densities were reduced in inhibitor groups versus controls. In summary, MIF promotes bladder cancer via increasing cell proliferation and angiogenesis and oral inhibitors of MIF may prove useful in treatment of this disease. © The Author 2013. Published by Oxford University Press.

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