Inhibitory effect of liposomal solutions of grape seed extract on the formation of heterocyclic aromatic amines.

The effectiveness of grape seed extract (GSE) encapsulated in liposomes to inhibit the formation of heterocyclic aromatic amines (HAA) during frying of beef patties was assessed. All liposomal systems were prepared by high pressure homogenization at 22 500 psi. A total of six samples (rapeseed oil (control), GSE at 0.1% and 0.2%, and GSE-containing liposomes with 1%, 2%, and 5% soy lecithin) were investigated. MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline), PhIP (2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine), Norharman, and Harman were found after the marinade application and frying. PhIP concentrations decreased upon marination with GSE (0.1%) and GSE-containing liposomes (1% and 5%) (p < 0.05). MeIQx contents decreased in all samples compared to the oil control (p < 0.01) while no effect on ß-carboline formation was observed. Results are in contrast to previous studies that had shown that liposomal encapsulation may enhance effectiveness of polyphenols to inhibit radical reactions. A mechanistic model was proposed to explain the observed differences.

Naive B-cell trafficking is shaped by local chemokine availability and LFA-1-independent stromal interactions.

It is not known how naive B cells compute divergent chemoattractant signals of the T-cell area and B-cell follicles during in vivo migration. Here, we used two-photon microscopy of peripheral lymph nodes (PLNs) to analyze the prototype G-protein-coupled receptors (GPCRs) CXCR4, CXCR5, and CCR7 during B-cell migration, as well as the integrin LFA-1 for stromal guidance. CXCR4 and CCR7 did not influence parenchymal B-cell motility and distribution, despite their role during B-cell arrest in venules. In contrast, CXCR5 played a nonredundant role in B-cell motility in follicles and in the T-cell area. B-cell migration in the T-cell area followed a random guided walk model, arguing against directed migration in vivo. LFA-1, but not α4 integrins, contributed to B-cell motility in PLNs. However, stromal network guidance was LFA-1 independent, uncoupling integrin-dependent migration from stromal attachment. Finally, we observed that despite a 20-fold reduction of chemokine expression in virus-challenged PLNs, CXCR5 remained essential for B-cell screening of antigen-presenting cells. Our data provide an overview of the contribution of prototype GPCRs and integrins during naive B-cell migration and shed light on the local chemokine availability that these cells compute.

Indoleamine 2,3-dioxygenase 1 (IDO1) activity correlates with immune system abnormalities in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a plasma cell malignancy with a multifaceted immune dysfunction. Indoleamine 2,3-dioxygenase 1 (IDO1) degrades tryptophan into kynurenine (KYN), which inhibits effector T cells and promote regulatory T-cell (Treg) differentiation. It is presently unknown whether MM cells express IDO1 and whether IDO1 activity correlates with immune system impairment. METHODS: We investigated IDO1 expression in 25 consecutive patients with symptomatic MM and in 7 patients with either monoclonal gammopathy of unknown significance (MGUS; n=3) or smoldering MM (SMM; n=4). IDO1-driven tryptophan breakdown was correlated with the release of hepatocyte growth factor (HGF) and with the frequency of Treg cells and NY-ESO-1-specific CD8(+) T cells. RESULTS: KYN was increased in 75% of patients with symptomatic MM and correlated with the expansion of CD4(+)CD25(+)FoxP3(+) Treg cells and the contraction of NY-ESO-1-specific CD8(+) T cells. In vitro, primary MM cells promoted the differentiation of allogeneic CD4(+) T cells into bona fide CD4(+)CD25(hi)FoxP3(hi) Treg cells and suppressed IFN-γ/IL-2 secretion, while preserving IL-4 and IL-10 production. Both Treg expansion and inhibition of Th1 differentiation by MM cells were reverted, at least in part, by D,L-1-methyl-tryptophan, a chemical inhibitor of IDO. Notably, HGF levels were higher within the BM microenvironment of patients with IDO(+) myeloma disease compared with patients having IDO(-) MM. Mechanistically, the antagonism of MET receptor for HGF with SU11274, a MET inhibitor, prevented HGF-induced AKT phosphorylation in MM cells and translated into reduced IDO protein levels and functional activity. CONCLUSIONS: These data suggest that IDO1 expression may contribute to immune suppression in patients with MM and possibly other HGF-producing cancers.

Comprehensive analysis of lymph node stroma-expressed Ig superfamily members reveals redundant and nonredundant roles for ICAM-1, ICAM-2, and VCAM-1 in lymphocyte homing.

Although it is well established that stromal intercellular adhesion molecule-1 (ICAM-1), ICAM-2, and vascular cell adhesion molecule-1 (VCAM-1) mediate lymphocyte recruitment into peripheral lymph nodes (PLNs), their precise contributions to the individual steps of the lymphocyte homing cascade are not known. Here, we provide in vivo evidence for a selective function for ICAM-1 > ICAM-2 > VCAM-1 in lymphocyte arrest within noninflamed PLN microvessels. Blocking all 3 CAMs completely inhibited lymphocyte adhesion within PLN high endothelial venules (HEVs). Post-arrest extravasation of T cells was a 3-step process, with optional ICAM-1-dependent intraluminal crawling followed by rapid ICAM-1- or ICAM-2-independent diapedesis and perivascular trapping. Parenchymal motility of lymphocytes was modestly reduced in the absence of ICAM-1, while ICAM-2 and alpha4-integrin ligands were not required for B-cell motility within follicles. Our findings highlight nonredundant functions for stromal Ig family CAMs in shear-resistant lymphocyte adhesion in steady-state HEVs, a unique role for ICAM-1 in intraluminal lymphocyte crawling but redundant roles for ICAM-1 and ICAM-2 in lymphocyte diapedesis and interstitial motility.

The combination of transition metal ions and hydrogen-bonding interactions.

This feature article presents an overview of the types of hydrogen bonding interactions involving metal complexes and their functional effects. It shows with recent examples why hydrogen bonds have become a crucial functional and structural element in modern inorganic chemistry. The relevance of this combination in tackling current chemistry challenges such as energy production and the development of new materials and more effective catalysts, sensors and medicines is illustrated.

Complex formation between Zn2+ ion and 1,3-bis[bis(pyridin-2-ylmethyl)amino]propan-2-ol.

The dinucleating ligand 1,3-bis[bis(pyridin-2-ylmethyl)amino] propan-2-ol (I, LOH) is becoming of increasing interest due to the exceptional phosphate monoester binding and phosphate diester hydrolytic properties of its dizinc(II) complexes in water. Potentiometric pH titrations using a range of Zn:I ratios reveals the formation of mononuclear and dinuclear metal complexes. In fact, when the Zn:I ratio is 1:1 only mononuclear complexes are formed. Previous work reported the formation of only dinuclear species. Thus, the results presented here should be important to interpret correctly and more accurately phosphate ester binding and hydrolysis data. Moreover, based on these findings we suggest that the phosphate binding and hydrolytic properties of mixtures containing Zn(II) ions and I should depend not only on the pH but also on the Zn:I ratio used.