15-deoxyprostaglandin-j2 and Peritonitis

15-Deoxy-Δ. 15d-PGJ

Topics: Animals; CD36 Antigens; Gene Expression Regulation; Heme Oxygenase-1; Humans; Jurkat Cells; Macrophages; Mice; NF-E2-Related Factor 2; Peritonitis; Phagocytosis; Prostaglandin D2; RAW 264.7 Cells; Zymosan

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity through up-regulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces up-regulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear. Here we show that an environmental electrophile, 1,2-naphthoquinone (1,2-NQ), but not 15d-prostaglandin J

Topics: Animals; Antineoplastic Agents; Cells, Cultured; Gene Expression Regulation; HEK293 Cells; Hep G2 Cells; Humans; Hydrogen Peroxide; Interleukin-11; Interleukin-11 Receptor alpha Subunit; Intestinal Diseases; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthoquinones; NF-E2-Related Factor 2; Oxidants; Oxidative Stress; Peritonitis; Prostaglandin D2; Reactive Oxygen Species

15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has physiological properties including pronounced anti-inflammatory activity, though it binds strongly to serum albumin. The use of solid lipid nanoparticles (SLN) can improve therapeutic properties increasing drug efficiency and availability. 15d-PGJ2-SLN was therefore developed and investigated in terms of its immunomodulatory potential. 15d-PGJ2-SLN and unloaded SLN were physicochemically characterized and experiments in vivo were performed. Animals were pretreated with 15d-PGJ2-SLN at concentrations of 3, 10 or 30 μg·kg-1 before inflammatory stimulus with carrageenan (Cg), lipopolysaccharide (LPS) or mBSA (immune response). Interleukins (IL-1β, IL-10 and IL-17) levels were also evaluated in exudates. The 15d-PGJ2-SLN system showed good colloidal parameters and encapsulation efficiency of 96%. The results showed that the formulation was stable for up to 120 days with low hemolytic effects. The 15d-PGJ2-SLN formulation was able to reduce neutrophil migration in three inflammation models tested using low concentrations of 15d-PGJ2. Additionally, 15d-PGJ2-SLN increased IL-10 levels and reduced IL-1β as well as IL-17 in peritoneal fluid. The new 15d-PGJ2-SLN formulation highlights perspectives of a potent anti-inflammatory system using low concentrations of 15d-PGJ2.

Topics: Animals; Anti-Inflammatory Agents; BALB 3T3 Cells; Carrageenan; Cell Survival; Gene Expression Regulation; Interleukins; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Nanoparticles; Neutrophil Infiltration; Particle Size; Peritonitis; Prostaglandin D2

The PPAR-γ agonist 15d-PGJ₂ is a potent anti-inflammatory agent but only at high doses. To improve the efficiency of 15d-PGJ₂, we used poly(D,L-lactide-co-glycolide) nanocapsules to encapsulate it, and function as a drug carrier system. The effects of these loaded nanocapsules (15d-PGJ₂-NC) on inflammation induced by different stimuli were compared with those of free 15d-PGJ₂.. Mice were pretreated (s.c.) with either 15d-PGJ₂-NC or unloaded 15d-PGJ₂ (3, 10 or 30 µg·kg⁻¹), before induction of an inflammatory response by i.p. injection of either endotoxin (LPS), carrageenan (Cg) or mBSA (immune response).. The 15d-PGJ₂-NC complex did not display changes in physico-chemical parameters or drug association efficiency over time, and was stable for up to 60 days of storage. Neutrophil migration induced by i.p. administration of LPS, Cg or mBSA was inhibited by 15d-PGJ₂-NC, but not by unloaded 15d-PGJ₂. In the Cg model, 15d-PGJ₂-NC markedly inhibited serum levels of the pro-inflammatory cytokines TNF-α, IL-1β and IL-12p70. Importantly, 15d-PGJ₂-NC released high amounts of 15d-PGJ₂, reaching a peak between 2 and 8 h after administration. 15d-PGJ ₂ was detected in mouse serum after 24 h, indicating sustained release from the carrier. When the same concentration of unloaded 15d-PGJ₂ was administered, only small amounts of 15d-PGJ₂ were found in the serum after a few hours.. The present findings clearly indicate the potential of the novel anti-inflammatory 15d-PGJ₂ carrier formulation, administered systemically. The formulation enables the use of a much smaller drug dose, and is significantly more effective compared with unloaded 15d-PGJ₂.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biocompatible Materials; Carrageenan; Cytokines; Drug Carriers; Hemoglobins; Immunization; Inflammation; Lactic Acid; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Nanocapsules; Neutrophil Infiltration; Neutrophils; Particle Size; Peritonitis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostaglandin D2; Serum Albumin, Bovine

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Chronic Disease; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Lipid Metabolism; Lipids; Lymphocytes; Mice; Models, Biological; Peritonitis; Prostaglandin D2; Time Factors