stearates and Inflammation

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that can effectively control the pain and inflammation caused by rheumatoid arthritis (RA), but its usage is limited due to severe adverse effects. For this reason, making more specific formulations of this drug can be considered. The aim of the present study was designing a novel nano-sized indomethacin delivery system.. Indomethacin-loaded dextran stearate polymeric micelles were prepared by dialysis method. Particle size and zeta potential of micelles were measured by a zeta sizer instrument. Drug release from micelles was investigated in phosphate buffer medium pH 7.4 and then the best formulation regarding physical properties and drug release was selected for animal studies. Arthritis was induced by complete Freund's adjuvant injection in rats. Then, the animals were randomly assigned into the model, the indomethacin solution and the polymeric micelles groups. The clinical effects of polymeric micelle formulation were assessed by measuring arthritis index, animal paw edema and measuring biochemical parameters including myeloperoxidase (MPO) activity, lipid peroxidation (LPO), glutathione (GSH), total antioxidant capacity (TAC), TNF-α, IL-17 and IL-1β.. Paw edema was attenuated following the administration of indomethacin-loaded polymeric micelles. Based on the findings of the present study, the use of indomethacin-loaded polymeric micelles could improve inflammatory symptoms, decrease arthritis index and decrease the diameter of the paw in arthritic rats in a significant manner (p ≤ 0.05). In addition, the use of polymeric micelles like indomethacin solution significantly reduced (p ≤ 0.05) the activity of MPO, LPO, TNF-α, IL-17 and IL-1β, and made a significant increase (p ≤ 0.05) in glutathione and TAC content and ameliorated structural changes in the paw tissue compared to the control group.. Our findings demonstrated that indomethacin-loaded dextran stearate polymeric micelles can provide more effective therapeutic effects in control of inflammation in arthritis in rat.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Dextrans; Drug Delivery Systems; Drug Liberation; Edema; Freund's Adjuvant; Indomethacin; Inflammation; Male; Micelles; Polymers; Rats; Rats, Wistar; Stearates

The targeting ability of pentapeptide (Thr-Lys-Pro-Pro-Arg) grafted nanostructured lipid carriers (Pen-NLCs) to macrophages was investigated in both in vitro and in vivo studies. The results showed the improvement of the anti-inflammatory effect by using this drug delivery system. Firstly, a pentapeptide-polyethylene glycol2000-stearate was synthesized and formulated into Pen-NLCs. Non-grafted nanostructured lipid carriers (Bare-NLCs) and Pen-NLCs were 190.0±1.0 and 203.0±8.5 nm in size, -8.1±2.1 and 2.3±1.2 mV in zeta potential respectively. Meanwhile, they had comparable entrapment efficiency and drug loading efficiency. In vitro and in vivo cellular uptake studies showed increased internalization of Pen-NLCs by macrophages when compared to pure drugs and Bare-NLCs. Animal studies in a carrageenan-treated air pouch model were used to further investigate the anti-inflammatory effects of Pen-NLCs. Through intravenous administration, a single dose of DXM loaded Pen-NLCs showed the strongest inhibition of inflammatory indexes of air pouch fluid weight, leukocyte infiltration, granulation tissue weight and nitric oxide concentration in comparison with free drugs and DXM loaded Bare-NLCs. In conclusion, this study demonstrated the potential of Pen-NLCs as promising drug carriers for anti-inflammatory treatments.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cell Line; Dexamethasone; Drug Carriers; Inflammation; Leukocyte Count; Macrophages; Male; Mice; Nanostructures; Nitric Oxide; Oligopeptides; Polyethylene Glycols; Rats; Rats, Wistar; Stearates

Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of the MAPK and NF-κB pathways in L6 myotubes, along with impaired insulin signalling and glucose transport. TAK-242 completely prevented the inflammatory response (MAPK and NF-κB activation) caused by LPS, and, in turn, improved LPS-induced insulin resistance. Similar to LPS, stearate strongly activated MAPKs, although stimulation of the NF-κB axis was modest. As seen with LPS, the inflammatory response caused by stearate was accompanied by impaired insulin action. TAK-242 also blunted stearate-induced inflammation; yet, the protective effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently, the insulin resistance caused by stearate was only partially improved by TAK-242. In summary, TAK-242 provides complete and partial protection against LPS- and NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced insulin resistance depends entirely on TLR4, whereas NEFA works through TLR4-dependent and -independent mechanisms to impair insulin action.

Topics: Animals; Biological Transport; Calcium-Binding Proteins; Cell Line; DNA-Binding Proteins; Dose-Response Relationship, Drug; Glucose; Inflammation; Insulin; Insulin Resistance; Lipopolysaccharides; MAP Kinase Signaling System; Muscle Fibers, Skeletal; Myoblasts; Nerve Tissue Proteins; Nucleobindins; Phosphorylation; Rats; Stearates; Sulfonamides; Time Factors; Toll-Like Receptor 4; Transcription Factor RelA

Four long-chain, linear fatty acid dopamides (N-acyldopamines) have been identified in nervous bovine and rat tissues. Two unsaturated members of this family of lipids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine, were shown to potently activate the transient receptor potential channel type V1 (TRPV1), also known as the vanilloid receptor type 1 for capsaicin. However, the other two congeners, N-palmitoyl- and N-stearoyl-dopamine (PALDA and STEARDA), are inactive on TRPV1. We have investigated here the possibility that the two compounds act by enhancing the effect of NADA on TRPV1 ('entourage' effect). When pre-incubated for 5 min with cells, both compounds dose-dependently enhanced NADA's TRPV1-mediated effect on intracellular Ca(2+) in human embryonic kidney cells overexpressing the human TRPV1. In the presence of either PALDA or STEARDA (0.1-10 microm), the EC(50) of NADA was lowered from approximately 90 to approximately 30 nm. The effect on intracellular Ca(2+) by another endovanilloid, N-arachidonoyl-ethanolamine (anandamide, 50 nm), was also enhanced dose-dependently by both PALDA and STEARDA. PALDA and STEARDA also acted in synergy with low pH (6.0-6.7) to enhance intracellular Ca(2+) via TRPV1. When co-injected with NADA (0.5 micrograms) in rat hind paws, STEARDA (5 micrograms) potentiated NADA's TRPV1-mediated nociceptive effect by significantly shortening the withdrawal latencies from a radiant heat source. STEARDA (1 and 10 micrograms) also enhanced the nocifensive behavior induced by carrageenan in a typical test of inflammatory pain. These data indicate that, despite their inactivity per se on TRPV1, PALDA and STEARDA may play a role as 'entourage' compounds on chemicophysical agents that interact with these receptors, with possible implications in inflammatory and neuropathic pain.

Topics: Animals; Arachidonic Acids; Calcium; Carrageenan; Cell Line; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Endocannabinoids; Hindlimb; Humans; Hyperalgesia; Inflammation; Italy; Kidney; Male; Pain Measurement; Palmitates; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Drug; Stearates; TRPV Cation Channels

Endovascular neurosurgery is now becoming available as one of strategies for the treatment of cerebro-spinal arterio-venous malformations and aneurysms. For this treatment, a microcatheter is advanced into or close to a lesion and then an embolic material is administered through it to obliterate the lesion. N-butyl-2-cyanoacrylate (NBCA) has preferentially been used as an embolic material in Europe and America. However, its exceptionally strong adhesive force sometimes causes adhesion between the tip of the microcatheter and the artery. In this study, a new non-adhesive cyanoacrylate, isostearyl-2-cyanoacrylate (ISCA), was developed. It carries a long hydrophobic side isostearyl group with lower reactivity and adhesion than other cyanoacrylates. Its polymerization rate is, however, too low to obliterate a vascular lesion with a rapid blood flow. To increase the polymerization rate. ISCA was mixed with NBCA. As a result, the adhesive force of the mixture became extremely low, compared with that of NBCA. The viscosity of the mixture was low enough to allow its' use as an embolic material. Tissue reactions against the mixture was milder than those against NBCA. Radio-angiography became possible by mixing further with Lipiodol. The evaluation of this new embolic material with a rabbit renal artery showed that the obliteration effect of the mixture of ISCA and NBCA was excellent to use as an embolic material for clinical applications.

Topics: Animals; Biocompatible Materials; Carotid Arteries; Cyanoacrylates; Embolization, Therapeutic; Enbucrilate; Inflammation; Kidney; Neurosurgical Procedures; Rabbits; Skin; Stearates; Stress, Mechanical; Swine; Tissue Adhesives; Vascular Surgical Procedures; Viscosity

Topics: Choline; Humans; Inflammation; Stearates; Stearic Acids