Diet-induced obesity reduces the production of influenza vaccine-induced antibodies via impaired macrophage function.

Obesity is a metabolic disease characterized by low-level chronic inflammation. Obese individuals are susceptible to infection by viruses, and vaccination against these pathogens is less effective than in nonobese individuals. Here, we sought to explore the immunological environment in a mouse model of obesity induced by a high-fat diet (HFD). HFD treatment increased the body weight and epididymal fat mass. The proportion of activated B cells, T cells, and macrophages was similar between mice in the HFD group and the regular-fat diet (RFD) group. The Th1 cell subpopulation in the HFD group was increased, whereas the proportion of Treg cells was reduced compared with the RFD group. Moreover, T-cell proliferation and cytokine production did not differ between the groups when cells were stimulated with anti-CD3 and anti-CD28 antibodies in vitro. In macrophages, phagocytic activity was higher in mice fed an HFD than in those fed an RFD, but expression levels of CD86 and MHC class II antigens were similar. When macrophages were cultured in vitro, the proportion of CD86-expressing macrophages was lower in those isolated from mice in the HFD group than in those isolated from the RFD group. Furthermore, lipopolysaccharide-induced interleukin 6 (IL-6) and tumor necrosis factor alpha secretions were significantly reduced in macrophages isolated from the HFD group. In addition, influenza vaccine-induced antibodies in the HFD group diminished more rapidly than in the RFD group. These results suggest that poor functionality of macrophages during obesity might contribute to a reduction in vaccine efficacy.

Characteristics of adipose tissue macrophages and macrophage-derived insulin-like growth factor-1 in virus-induced obesity.

BACKGROUND: Various pathogens are implicated in the induction of obesity. Previous studies have confirmed that human adenovirus 36 (Ad36) is associated with increased adiposity, improved glycemic control and induction of inflammation. The Ad36-induced inflammation is reflected in the infiltration of macrophages into adipose tissue. However, the characteristics and role of adipose tissue macrophages (ATMs) and macrophage-secreted factors in virus-induced obesity (VIO) are unclear. Although insulin-like growth factor-1 (IGF-1) is involved in obesity metabolism, the contribution of IGF secreted by macrophages in VIO has not been studied. METHODS: Four-week-old male mice were studied 1 week and 12 weeks after Ad36 infection for determining the characteristics of ATMs in VIO and diet-induced obesity (DIO). In addition, macrophage-specific IGF-1-deficient (MIKO) mice were used to study the involvement of IGF-1 in VIO. RESULTS: In the early stage of VIO (1 week after Ad36 infection), the M1 ATM sub-population increased, which increased the M1/M2 ratio, whereas DIO did not cause this change. In the late stage of VIO (12 weeks after Ad36 infection), the M1/M2 ratio did not change because the M1 and M2 ATM sub-populations increased to a similar extent, despite an increase in adiposity. By contrast, DIO increased the M1/M2 ratio. In addition, VIO in wild-type mice upregulated angiogenesis in adipose tissue and improved glycemic control. However, MIKO mice showed no increase in adiposity, angiogenesis, infiltration of macrophages into adipose tissue, or improvement in glycemic control after Ad36 infection. CONCLUSIONS: These data suggest that IGF-1 secreted by macrophages may contribute to hyperplasia and hypertrophy in adipose tissue by increasing angiogenesis, which helps to maintain the 'adipose tissue robustness'.

The pharmacokinetics, pharmacodynamics and safety of oral doses of ilaprazole 10, 20 and 40 mg and esomeprazole 40 mg in healthy subjects: a randomised, open-label crossover study.

BACKGROUND: Ilaprazole, a proton pump inhibitor (PPI) currently in clinical use, may provide improved acid suppression vs. other PPIs. AIM: To compare the pharmacodynamic and pharmacokinetic profiles of ilaprazole and esomeprazole. METHODS: A phase 1, randomised, open-label, single-centre, 4-period crossover study was conducted in 40 healthy volunteers. Ilaprazole 10, 20 or 40 mg or esomeprazole 40 mg was administered once daily for 5 days with ≥5-day washout intervals. Pharmacokinetic blood samples and intragastric pH measurements were collected at scheduled timepoints for 24 h after dosing on Days 1 and 5. RESULTS: Esomeprazole 40 mg provided significantly better pH control during the initial hours (0-4 h) after a single dose, but ilaprazole (particularly 20 and 40 mg) provided significantly better pH control for the entire 24-h period and during evening and overnight hours after single and multiple doses. Increasing ilaprazole doses resulted in dose-proportional increases in peak plasma concentration and area under the plasma concentration vs. time curve following single and multiple doses. Ilaprazole was safe and generally well tolerated; an unexpectedly high incidence of allergic eye and skin reactions were observed but were not specific to any dosing regimen. Plasma gastrin concentrations did not increase proportionately with increasing ilaprazole dose. CONCLUSIONS: Ilaprazole provided significantly better pH control over 24 h and during evening and overnight hours compared with esomeprazole in healthy volunteers, which may translate to greater relief of night-time heartburn in the clinical setting for patients with gastric acid-related disorders.

Microphotoluminescence spectroscopy of single CdTe/ZnTe quantum dots grown on Si001 substrates.

We have studied the emission properties of single CdTe/ZnTe quantum dots (QDs) grown on Si(001) substrates by using molecular beam epitaxy and atomic layer epitaxy. The good quality of the QDs is attested by the resolution-limited emission, negligible background and absence of measurable spectral jitter or blinking. Power-dependent, polarization-dependent, and temperature-dependent microphotoluminescence spectroscopy measurements were performed to identify the exciton, the biexciton, and two oppositely charged excitons in the emission spectra of single QDs.

Anti-lipid peroxidative principles from the stem bark of Kalopanax pictus Nakai.

Hepatic lipid peroxide contents were examined in bromobenzene-treated rats firstly after the oral administration of MeOH extract of Kalopanax pictus stem barks, its n-BuOH fraction, EtOAc fraction and an alkaline hydrolysate of the n-BuOH fraction, and secondly after the intraperitoneal administration of hederagenin monodesmosides and bisdesmosides. Two hederagenin monodesmosides, kalopanaxsaponin A (KPS-A) and sapindoside C, exhibited significant anti-lipid peroxidation effects after intraperitoneal administration at doses of 10-30 micromole/kg, whereas their bisdesmosides did not exhibit any significant activity. These results suggest that it is the hederagenin monodesmosides that are responsible for anti-lipid peroxidation in vivo. The activity of KPS-A was established by the observation of decreased aminopyrine N-demethylase activity and increased epoxide hydrolase activity.

Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation.

The secreted factor Sonic hedgehog (SHH) is both required for and sufficient to induce multiple developmental processes, including ventralization of the CNS, branching morphogenesis of the lungs and anteroposterior patterning of the limbs. Based on analogy to the Drosophila Hh pathway, the multiple GLI transcription factors in vertebrates are likely to both transduce SHH signaling and repress Shh transcription. In order to discriminate between overlapping versus unique requirements for the three Gli genes in mice, we have produced a Gli1 mutant and analyzed the phenotypes of Gli1/Gli2 and Gli1/3 double mutants. Gli3(xt) mutants have polydactyly and dorsal CNS defects associated with ectopic Shh expression, indicating GLI3 plays a role in repressing Shh. In contrast, Gli2 mutants have five digits, but lack a floorplate, indicating that it is required to transduce SHH signaling in some tissues. Remarkably, mice homozygous for a Gli1(zfd )mutation that deletes the exons encoding the DNA-binding domain are viable and appear normal. Transgenic mice expressing a GLI1 protein lacking the zinc fingers can not induce SHH targets in the dorsal brain, indicating that the Gli1(zfd )allele contains a hypomorphic or null mutation. Interestingly, Gli1(zfd/zfd);Gli2(zfd/+), but not Gli1(zfd/zfd);Gli3(zfd/+) double mutants have a severe phenotype; most Gli1(zfd/zfd);Gli2(zfd/+) mice die soon after birth and all have multiple defects including a variable loss of ventral spinal cord cells and smaller lungs that are similar to, but less extreme than, Gli2(zfd/zfd) mutants. Gli1/Gli2 double homozygous mutants have more extreme CNS and lung defects than Gli1(zfd/zfd);Gli2(zfd/+) mutants, however, in contrast to Shh mutants, ventrolateral neurons develop in the CNS and the limbs have 5 digits with an extra postaxial nubbin. These studies demonstrate that the zinc-finger DNA-binding domain of GLI1 protein is not required for SHH signaling in mouse. Furthermore, Gli1 and Gli2, but not Gli1 and Gli3, have extensive overlapping functions that are likely downstream of SHH signaling.

Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system.

Induction of the floor plate at the ventral midline of the neural tube is one of the earliest events in the establishment of dorsoventral (d/v) polarity in the vertebrate central nervous system (CNS). The secreted molecule, Sonic hedgehog, has been shown to be both necessary and sufficient for this induction. In vertebrates, several downstream components of this signalling pathway have been identified, including members of the Gli transcription factor family. In this study, we have examined d/v patterning of the CNS in Gli2 mouse mutants. We have found that the floor plate throughout the midbrain, hindbrain and spinal cord does not form in Gli2 homozygotes. Despite this, motoneurons and ventral interneurons form in their normal d/v positions at 9.5 to 12.5 days postcoitum (dpc). However, cells that are generated in the region flanking the floor plate, including dopaminergic and serotonergic neurons, were greatly reduced in number or absent in Gli2 homozygous embryos. These results suggest that early signals derived from the notochord can be sufficient for establishing the basic d/v domains of cell differentiation in the ventral spinal cord and hindbrain. Interestingly, the notochord in Gli2 mutants does not regress ventrally after 10.5 dpc, as in normal embryos. Finally, the spinal cord of Gli1/Gli2 zinc-finger-deletion double homozygous mutants appeared similar to Gli2 homozygotes, indicating that neither gene is required downstream of Shh for the early development of ventral cell fates outside the ventral midline.

Synergistic roles of granzymes A and B in mediating target cell death by rat basophilic leukemia mast cell tumors also expressing cytolysin/perforin.

We have studied the cytotoxic activity of rat basophilic leukemia (RBL) cells transfected with cDNAs for the cytotoxic T lymphocyte (CTL) granule components, cytolysin (perforin), granzyme A, and granzyme B. With red cell targets, cytolysin expression conferred potent hemolytic activity, which was not influenced by coexpression of granzymes. With tumor targets, RBL cells expressing cytolysin alone were weakly cytotoxic, but both cytolytic and nucleolytic activity were enhanced by coexpression of granzyme B. RBL cells expressing all three CTL granule components showed still higher cytotoxic activities, with apoptotic target death. Analysis of the cytotoxic activity of individual transfectant clones showed that cytolytic and nucleolytic activity correlated with granzyme expression but was independent of cytolysin expression within the range examined. A synergism between granzymes A and B was apparent when the triple transfectant was compared with RBL cells expressing cytolysin and one granzyme. These data implicate granzymes as the major mediators of tumor target damage by cytotoxic lymphocytes.