Sepsis is a clinical syndrome defined as a systemic inflammatory response to infection. Eritoran is a synthetic lipid A derivative that competes with lipopolysaccharide in binding to the identical site of myeloid differentiation-2/toll-like receptor 4 complex. Eritoran is effective in decreasing the septic mortality of Gram-negative bacteria-infected animals. Eritoran has been highlighted as a candidate drug for treatment of endotoxemia in phase I clinical studies with healthy human volunteers. A phase II trial of eritoran has been conducted in patients with severe sepsis. Intravenous infusion of eritoran reduced the mortality rate, as compared with the placebo group, in sepsis patients at a high risk of mortality according to acute physiology and chronic health evaluation-II scores. A phase III study of eritoran was completed in 2011. The results appear to be disappointing as no statistically significant difference in all-cause mortality was observed between the eritoran treatment group and the placebo group on day 28 in sepsis patients with a high risk of death. In this review, we focus on the rationale for the use of eritoran in treatment of sepsis as well as its clinical applications.

Effects of carnitine on atherosclerosis and steatosis of hypercholesterolemic rabbits induced by a high-cholesterol diet (HCD) containing 0.5% cholesterol and 2.0% corn oil were investigated. Male New Zealand white rabbits with hypercholesterolemia (blood cholesterol 1,000-1,500 mg/dl) induced by two-week feeding a HCD, were fed a HCD containing 0.008 or 0.075% L-carnitine for an additional eight weeks. Feeding a HCD for 10 weeks resulted in severe atheromatous change, covering 55.7% of the aortic walls, in addition to profound hepatic steatosis. However, carnitine supplementation resulted in recovery of the increased low-density lipoproteins and triglycerides and a decrease in the levels of high-density lipoproteins following HCD feeding, although the increased cholesterol concentration was not potentially attenuated. Notably, carnitine induced a marked reduction of the atheroma area and hepatic lipid accumulation as well as lipid peroxidation. The results of this study indicated that carnitine exerted anti-atherosclerotic and fatty liver-preventing activities through blockade of lipid peroxidation and regulation of lipid metabolism.

Neurotoxicity and oxidative injury induced by glutamate cause neuronal degeneration related to various central nervous system diseases. Resveratrol, a polyphenolic compound, is known to have antioxidative and anti-inflammatory effects. The aim of this study was to investigate the question of whether resveratrol has a neuroprotective effect against glutamate-induced toxicity in cultured cortical neurons. Following exposure to glutamate for 15 min, cortical neurons originating from ICR mouse fetuses on embryonic days 15-16 were then treated with resveratrol for 24 h in the post-treatment paradigm. Glutamate induced a significant reduction in cell viability; however, resveratrol induced a significant increase in cell viability. Glutamate induced generation of ROS and apoptotic neuronal death; however, these were decreased by exposure to resveratrol. mRNA expression in antioxidant enzymes, cytoplasmic glutathione peroxidase, copper/zinc superoxide dismutase (SOD), and manganese SOD, and anti-apoptotic regulator Bcl-xL were decreased by exposure to glutamate, however, exposure to resveratrol resulted in a significant increase in their mRNA levels. In addition, mRNA expression of pro-inflammatory cytokines, interleukin-1β and tumor necosis factor-α, was increased by glutamate insult, but significantly reduced by resveratrol. These findings indicate that resveratrol is neuroprotective against glutamate-induced toxicity, suggesting a useful therapeutic application in treatment of neurodegenerative disorders.

To investigate the effect of carnosine on exhaustive exercise, swimming tests were conducted weekly with loads corresponding to 5% of body weight attached to the tails of mice, and the swimming time to exhaustion was measured. Eighty male ICR mice were divided into four groups, to which carnosine was administered at doses of 0 (control), 10, 50, and 250 mg/kg/day, respectively, for a period of four weeks. At the end of swimming exercise challenges, serum biochemistry, oxidative stress enzyme activity, and antioxidant enzyme activity in tissues were determined. Treatment with 250 mg/kg carnosine resulted in a significant increase in swimming times to exhaustion, compared to the control group in the first (P<0.01) and third week (P<0.05). Significantly lower serum lactate levels were observed after the swimming exercise in the carnosine-treated groups (10 and 250 mg/kg), compared with the control (P<0.01). Malondialdehyde levels in the liver (10 and 50 mg/kg carnosine treated groups) and skeletal muscle (250 mg/kg carnosine treated group) were significantly lower, compared with the control (P<0.05). Significantly lower protein carbonyl levels in skeletal muscle were observed in the 50 and 250 mg/kg carnosine treated groups, compared with the control (P<0.01). Superoxide dismutase and glutathione peroxidase activities in skeletal muscle did not differ significantly among the groups. These results indicate that carnosine may improve swimming exercise capacity by attenuating production of lactate and reducing oxidative stress in mice.

We investigated free radical reactions in lung of living mice using an in vivo electron spin resonance (ESR) spectrometer and nitroxyl radical as a probe. When an aqueous solution of nitroxyl probe was trans-tracheally administered into lung of living mice, a sharp triplet signal was observed at the chest of the mice. The signal showed a gradual decrease with time, obeying first-order kinetics. Signal decay rates of carbamoyl-PROXYL and carboxy-2,2,6,6-tetramethyl-piperidine-N-oxyl were faster than those of CAT-1 and carboxy-PROXYL. The mechanism of signal decay may be attributed to (i) reaction with reactive oxygen species such as ·OH, (ii) transfer into blood circulation, or (iii) reduction by compounds continuously supplied. However, little is known about the clearance mechanism of the nitroxyl probe in lung. To evaluate the disappearance of the ESR signal of the nitroxyl probe in lung, in vivo ESR spectra in chest of mice was recorded after trans-tracheal administration of an aqueous high concentrate solution of nitroxyl probe. A broad signal from the chest was observed immediately after administration due to Heisenberg spin exchange interaction. A sharp triplet signal was superimposed on the broad signal and the appearance of a triplet signal was followed by disappearance of the broad one. Peak-to-peak line width of the sharp signal was almost the same as that after intravenous administration. A distinct signal was detected in blood collected 10 min after trans-tracheal administration of nitroxyl probe. The observations indicate the transfer from lung to blood circulation and its contribution to clearance of probe in lung. Appearance of a sharp signal in blood after trans-tracheal administration was dependent on the kind of nitroxyl probe, showing a different transfer rate from lung to blood.

Canine heartworm disease is typically characterized by the presence of heartworms in the pulmonary artery and, to a lesser degree, the right ventricle. Systemic arterial dirofilariasis is an unusual manifestation of heartworm disease of dogs that results from aberrant migration of Dirofilaria immitis into the peripheral arterial circulation. A three-year-old Jindo dog was referred to the Veterinary Medical Center because of hindlimb lameness, paresthesia of hindlimbs, and interdigital ischemic necrosis. Angiography and ultrasonography were performed, resulting in diagnosis of heartworm infestation. In necropsy, entangled heartworms were present throughout the body, including lungs, kidney, small intestinal lumen, and arteries, in addition to the right ventricle and pulmonary artery. Histologically, lung showed adult heart worms in vessels, organized thrombotic vessels, and interstitial pneumonia featuring type II pneumocyte hyperplasia, thickened alveolar wall, and compressed alveolar spaces. Chronic parenchymal lesions, such as focal or diffuse necrosis, fibrosis, and dystrophic calcification were remarkable in liver and kidney. The current case showed a typical canine systemic heartworm disease caused by aberrant migration of Dirofilaria immitis.