Recent advances in the etiology and treatment of inflammatory bowel disease

Crohn’s disease and ulcerative colitis, together comprising the inflammatory bowel diseases, currently affect up to 2 million people in the western developed countries. The pathogenesis of the disease is a complex one in which genetic, immunogenic, microbial and environmental factors contribute to the etiology of the disease. Recent advances in understanding the molecular mechanisms that determine this complex entity have provided insight for promising new therapies.     

Interleukin-15 in the treatment of cancer

IL-15 is a 14–15 kDa member of the four α-helix bundle of cytokines that acts through a heterotrimeric receptor involving IL-2/IL-15R β, γc and the IL-15 specific receptor subunit IL-15R α. IL-15 stimulates the proliferation of T, B and NK cells, and induces stem, central and effector memory CD8 T cells. In rhesus macaques, continuous infusion of recombinant human IL-15 at 20 μg/kg/day was associated with approximately a 10-fold increase in the numbers of circulating NK, γ/δ cells and monocytes, and an 80- to 100-fold increase in the numbers of effector memory CD8 T cells. IL-15 has shown efficacy in murine models of malignancy. Clinical trials involving recombinant human IL-15 given by bolus infusions have been completed and by subcutaneous and continuous intravenous infusions are underway in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL-15 with IL-15R α^+/- IgFc.     

Type 1 reaction in leprosy: a model for a better understanding of tissue immunity under an immunopathological condition

Type 1 reaction (T1R) or reversal reaction is the leading cause of physical disabilities and deformities in leprosy. Leprosy patients, even after being considered cured and released from treatment, may suffer from reactional episodes for long periods of time. Early diagnosis is a great challenge for effectively treating and managing T1R. There is an urgent need to identify the most significant biomarkers to prevent recurrent T1R and to differentiate late T1R from relapse. T1R continues to be treated with corticosteroids and complications due to iatrogenic treatment remain frequent. This review aims to provide a framework from which to approach the great challenges that still persist in T1R management and debate key issues in order to reduce the distance between basic research and the clinic.     

Bacteriomimetic poly-γ-glutamic acid surface coating for hemocompatibility and safety of nanomaterials

Poly-γ-glutamic acid (PGA), a major component of the bacterial capsule, is known to confer hydrophilicity to bacterial surfaces and protect bacteria from interactions with blood cells. We tested whether applying a bacteriomimetic surface coating of PGA modulates interactions of nanomaterials with blood cells or affects their safety and photothermal antitumor efficacy. Amphiphilic PGA (APGA), prepared by grafting phenylalanine residues to PGA, was used to anchor PGA to reduced graphene oxide (rGO) nanosheets, a model of hydrophobic nanomaterials. Surface coating of rGO with bacterial capsule-like APGA yielded APGA-tethered rGO nanosheets (ArGO). ArGO nanosheets remained stable in serum over 4?weeks, whereas rGO in plain form precipitated in serum within 5?minutes. Moreover, ArGO did not interact with blood cells, whereas rGO in plain form or as a physical mixture with PGA formed aggregates with blood cells. Mice administered ArGO at a dose of 50?mg/kg showed 100% survival and no hepatic or renal toxicity. No mice survived exposure at the same dose of rGO or a PGA/rGO mixture. Following intravenous administration, ArGO showed a greater distribution to tumors and prolonged tumor retention compared with other nanosheet formulations. Irradiation with near-infrared light completely ablated tumors in mice treated with ArGO. Our results indicate that a bacteriomimetic surface modification of nanomaterials with bacterial capsule-like APGA improves the stability in blood, biocompatibility, tumor distribution, and photothermal antitumor efficacy of rGO. Although APGA was used here to coat the surfaces of rGO, it could be applicable to coat surfaces of other hydrophobic nanomaterials.     

Differential effects of PPARgamma agonists on the metabolic properties of gliomas and astrocytes

Recent studies show that thiazolinediones (TZDs), agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), induce apoptosis in glioma and glioblastoma cells. Here we compared the effects of troglitazone (Trog), a TZD with low affinity for binding to PPARgamma but with potent metabolic effects, on survival and metabolism in GL261 glioma cells versus primary astrocytes. Trog dose-dependently induced cell death in GL261 cells (with over 90% death at 30 microM) but did not cause any toxicity in astrocytes at the same doses. Measurements of glucose and lactate levels after incubation with Trog (30 microM) indicated an overall increase of glucose consumption and lactate production in both cell types. In astrocytes the ratio of lactate produced to glucose utilized was not significantly altered by Trog, while in glioma cells this ratio was decreased by about 40%. Trog dose-dependently reduced mitochondrial membrane potential (DeltaPsi(m)) in both cell types; and the loss of DeltaPsi(m) was greater in the tumor cells (90% loss at 20 microM) than in astrocytes (70% loss at 20 microM). These results suggest that differences in metabolic responses could contribute to the selective resistance of astrocytes to cytotoxic effects of Trog. TZDs such as Trog should therefore be considered for testing in treatment of gliomas.