Transfer of apolipoproteins between plasma lipoproteins and exogenous lipid particles after repeated bolus injections or during a continuous infusion of fat emulsion

Recent studies on the metabolism of artificial lipid particles in a fat emulsion (exo TG) revealed that exo TG acquired apolipoproteins in vivo and in vitro. In particular, apolipoproteins C-II and C-III (apo C-II and apo C-III) are rapidly transferred from high-density lipoprotein (HDL) to exo TG, and return to HDL after the hydrolysis of exo TG. The present study was undertaken to examine whether the movement of apo C-II and apo C-III between HDL and exo TG is influenced by a prior injection of fat emulsion. Two experiments were undertaken. In experiment 1, six male volunteers received three bolus injections of a fat emulsion at a dose of 0.1 g of TG/kg with intervals of 90 min between injections. In experiment 2, the plasma concentrations of triglycerides were maintained at approximately 500 mg/dl for 160 min by the continuous infusion of exo TG. Levels of apo C-II and apo C-III, and the elimination rate of exo TG were followed in each test. In experiment 1, the movement of apolipoproteins between exo TG and HDL was unchanged between the first, second, and third bolus. The elimination rate of exo TG after the third bolus was higher than that after the first bolus. In experiment 2, after the administration of exo TG, the levels of C apolipoproteins in the fraction of HDL began to decrease, and those in the fraction of very-low-density lipoprotein that contained exo TG began to increase. When the concentrations of triglycerides in plasma reached a plateau, the distribution of C apolipoproteins in the lipoprotein fraction also stabilized.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of an influx transporter in the blood–brain barrier transport of naloxone

Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood–brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [³H]naloxone exhibited saturability in a concentration‐dependent manner (concentration range 0.5 µM to 15 mM ) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier‐mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, K_t, was 2.99±0.71 mM ; the maximum uptake rate, J_max, was 0.477±0.083 µmol/min/g brain; and the nonsaturable first‐order rate constant, K_d, was 0.160±0.044 ml/min/g brain. The uptake of [³H]naloxone by the rat brain increased as the pH of the injected solution was increased from 5.5 to 8.5 and was strongly inhibited by cationic H₁‐antagonists such as pyrilamine and diphenhydramine and cationic drugs such as lidocaine and propranolol. In contrast, the BBB transport of [³H]naloxone was not affected by any typical substrates for organic cation transport systems such as tetraethylammonium, ergothioneine or L ‐carnitine or substrates for organic anion transport systems such as p‐aminohippuric acid, benzylpenicillin or pravastatin. The present results suggest that a pH‐dependent and saturable influx transport system that is a selective transporter for cationic H₁‐antagonists is involved in the BBB transport of naloxone in the rat. Copyright © 2010 John Wiley & Sons, Ltd.     

Conjugation of acetaldehyde with cysteinylglycine,the first metabolite in glutathione breakdown byγ-glutamyltranspeptidase

Glutathione and its metabolites were examined for reactivity to acetaldehyde. When acetaldehyde was incubated with glutathione alone, there was only a slight decrease of acetaldehyde, while an apparently equimolar reaction between acetaldehyde and free sulfhydryl was observed with the addition of -glutamyltranspeptidase. Cysteinylglycine, the first metabolite in the glutathione breakdown by -glutamyltranspeptidase, showed a rapid and equimolar reactivity to acetaldehyde and such was comparable to the reaction seen withl-cysteine ord-penicillamine. In light of the chemical structure, cysteinylglycine probably conjugates with acetaldehyde to form thiazolidinecarboxylic acid derivatives, 2-methyl-thiazolidine-4-carbonyl-glycine, and if so, the alteration of glutathione metabolism by acetaldehyde during ethanol intoxication warrants further attention.     

Alteration of E-cadherin and beta-catenin in mouse vestibular epithelia during induction of apoptosis

The aim of this study was to examine if adhesion molecules had relation with degeneration and regeneration processes of mammalian vestibular epithelia. The distribution of E-cadherin and beta-catenin was immunohistochemically examined in normal and aminoglycoside-treated utricles of mice. E-cadherin and beta-catenin linearly expressed between epithelial cells in normal specimens. Aminoglycoside injury resulted in temporal alteration in distribution of these molecules with induction of apoptosis in hair cells. Degradation of both molecules was widely observed in vestibular epithelia, while some supporting cells exhibited accumulation of beta-catenin. After completion of induction of apoptosis, expression of these adhesion molecules was normal in distribution. These findings suggest that the E-cadherin-beta-catenin complex plays roles in degeneration and subsequent repair processes in vestibular epithelia affected by aminoglycosides.     

Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses

CD11b(+) Gr-1(+) immature myeloid cells (ImCs), which are abnormally increased in tumor-bearing mice, were classified into three different subsets according to their phenotypic and morphological characteristics: Gr-1(low) F4/80(+) macrophages (MΦ-ImCs), Gr-1(mid) stab neutrophils (Neut(stab)-ImCs), and Gr-1(high) segmented neutrophils (Neut(seg)-ImCs). In the spleen, only MΦ-ImCs but not Neut(stab)-ImCs and Neut(seg)-ImCs exhibited a significant immunosuppressive activity in MLR. In contrast, tumor-infiltrating leukocytes (TILs) contained only two ImC subsets, MΦ-ImCs and Neut(seg)-ImC, both of which exhibited stronger inhibitory activity against T cells compared with spleen-MΦ-ImCs. Thus, we concluded that tumor-infiltrating MΦ-ImCs and Neut(seg)-ImCs were fully differentiated myeloid-derived suppressor cells (MDSCs) with stronger T-cell inhibitory activity. Indeed, spleen MΦ-ImCs were converted into stronger MΦ-MDSCs by tumor-derived factor (TDF). Moreover, both spleen Neut(stab)-ImCs and Neut(seg)-ImCs differentiated into Neut(seg)-MDSCs with suppressive activity after culture with TDF. We first demonstrated that administration of anti-IL-6R mAb could downregulate the accumulation of MΦ-MDSCs and Neut(seg)-MDSCs in tumor-bearing mice. The elimination of those MDSCs caused subsequent enhancement of antitumor T-cell responses, including IFN-γ-production. The therapeutic effect of anti-IL-6R mAb was further enhanced by combination with gemcitabine (GEM). Thus, we propose that anti-IL-6R mAb could become a novel tool for the downmodulation of MDSCs to enhance antitumor T-cell responses in tumor-bearing hosts.     

Cholesterol granuloma of the posterior ethmoid sinus mimicking meningocele

Cholesterol granuloma is usually associated with chronic middle ear disease, less common in the orbit, and rare in the paranasal sinus. Cholesterol granuloma is thought to be initiated by hemorrhage, impaired drainage, and interruption of aeration. Here we report a case of cholesterol granuloma arising in the posterior ethmoid sinus mimicking meningocele. Magnetic resonance imaging is useful for differential diagnosis, and endoscopic surgery is effective for the management of cholesterol granuloma arising in the ethomoid sinus.