A selective small-molecule inhibitor of macrophage migration inhibitory factor-2 (MIF-2), a MIF cytokine superfamily member, inhibits MIF-2 biological activity.

Cytokine macrophage migration inhibitory factor-2 (MIF-2 or D-dopachrome tautomerase) is a recently characterized second member of the MIF cytokine superfamily in mammalian genomes. MIF-2 shares pro-inflammatory and tumorigenic properties with the clinical target MIF (MIF-1), but the precise contribution of MIF-2 to immune physiology or pathology is unclear. Like MIF-1, MIF-2 has intrinsic keto-enol tautomerase activity and mediates biological functions by engaging the cognate, common MIF family receptor CD74.

Galectin-3: A Harbinger of Reactive Oxygen Species, Fibrosis, and Inflammation in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease arising from the narrowing of pulmonary arteries (PAs) resulting in high pulmonary arterial blood pressure and ultimately right ventricle (RV) failure. A defining characteristic of PAH is the excessive and unrelenting inward remodeling of PAs that includes increased proliferation, inflammation, and fibrosis. There is no cure for PAH nor interventions that effectively arrest or reverse PA remodeling, and intensive research over the past several decades has sought to identify novel molecular mechanisms of therapeutic value.

Galectin-3 is expressed in vascular smooth muscle cells and promotes pulmonary hypertension through changes in proliferation, apoptosis, and fibrosis.

A defining characteristic of pulmonary hypertension (PH) is the extensive remodeling of pulmonary arteries (PAs), which results in progressive increases in vascular resistance and stiffness and eventual failure of the right ventricle. There is no cure for PH and identification of novel molecular mechanisms that underlie increased proliferation, reduced apoptosis, and excessive extracellular matrix production in pulmonary artery smooth muscle cells (PASMCs) is a vital objective. Galectin-3 (Gal-3) is a chimeric lectin and potent driver of many aspects of fibrosis, but its role in regulating PASMC behavior in PH remains poorly understood.

Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma.

This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity.

Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury.

Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury.

Triglyceride modulation by acifran analogs: activity towards the niacin high and low affinity G protein-coupled receptors HM74A and HM74.

Niacin is known to exert profound beneficial effects on cholesterol levels in humans, although its use is somewhat hampered by the gram quantities necessary to exert effects and the prevalence of compliance-limiting skin flushing side effects that occur. Recently, two G protein-coupled receptors (GPCRs) for niacin were identified and characterized as high (HM74A; GPR109A) and low (HM74; GPR109B) affinity receptors based on the binding affinities of niacin. These receptors also bind acifran (AY-25,712), which is known to modulate lipid levels like niacin, with similar affinities.

IL-11 protects human microvascular endothelium from alloinjury in vivo by induction of survivin expression.

IL-11 can reduce tissue injury in animal models of inflammation but the mechanism(s) is unknown. When C.B-17 SCID/beige mice bearing human skin grafts are injected i.

Interleukin-11 and interleukin-6 protect cultured human endothelial cells from H2O2-induced cell death.

Acute lung injury is a frequent and treatment-limiting consequence of therapy with 100% oxygen. Previous studies have determined that both interleukin (IL)-6 and IL-11 are protective in oxygen toxicity. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment.

Desensitization of signaling by oncostatin M in human vascular cells involves cytoplasmic Tyr residue 759 in gp130 but is not mediated by either Src homology 2 domain-containing tyrosine phosphatase 2 or suppressor of cytokine signaling 3.

Oncostatin M (OnM) signals through cell surface receptors, which utilize the gp130 subunit. In cultured human umbilical vein endothelial cells (HUVEC), OnM transiently elevates mRNA encoding for suppressor of cytokine signaling-3 (SOCS-3). By 1 h of OnM treatment, HUVEC become refractory to the restimulation by OnM, measured as failure to reinduce SOCS-3 mRNA.

Activation of signal transducer and activator of transcription 1 (STAT1) is not sufficient for the induction of STAT1-dependent genes in endothelial cells. Comparison of interferon-gamma and oncostatin M.

We compared human endothelial cell (EC) responses to interferon-gamma (IFN gamma) and oncostatin M (OnM), cytokines that utilize Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Both cytokines cause phosphorylation of Tyr residue 701 and Ser residue 727 of STAT1, as shown by immunoblotting. Both activate DNA binding of STAT1 homodimers, shown by electrophoretic mobility shift assay.