Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype

We recently demonstrated that ω-3-polyunsaturated fatty acids ameliorate obesity-induced adipose tissue inflammation and insulin resistance. In this study, we report novel mechanisms underlying ω-3-polyunsaturated fatty acid actions on adipose tissue, adipocytes, and stromal vascular cells (SVC). Inflamed adipose tissue from high-fat diet-induced obese mice showed increased F4/80 and CD11b double-positive macrophage staining and elevated IL-6 and MCP-1 levels. Docosahexaenoic acid (DHA; 4 μg/g) did not change the total number of macrophages but significantly reduced the percentage of high CD11b/high F4/80-expressing cells in parallel with the emergence of low-expressing CD11b/F4/80 macrophages in the adipose tissue. This effect was associated with downregulation of proinflammatory adipokines in parallel with increased expression of IL-10, CD206, arginase 1, resistin-like molecule α, and chitinase-3 like protein, indicating a phenotypic switch in macrophage polarization toward an M2-like phenotype. This shift was confined to the SVC fraction, in which secretion of Th1 cytokines (IL-6, MCP-1, and TNF-α) was blocked by DHA. Notably, resolvin D1, an anti-inflammatory and proresolving mediator biosynthesized from DHA, markedly attenuated IFN-γ/LPS-induced Th1 cytokines while upregulating arginase 1 expression in a concentration-dependent manner. Resolvin D1 also stimulated nonphlogistic phagocytosis in adipose SVC macrophages by increasing both the number of macrophages containing ingested particles and the number of phagocytosed particles and by reducing macrophage reactive oxygen species production. No changes in adipocyte area and the phosphorylation of hormone-sensitive lipase, a rate-limiting enzyme regulating adipocyte lipolysis, were observed. These findings illustrate novel mechanisms through which resolvin D1 and its precursor DHA confer anti-inflammatory and proresolving actions in inflamed adipose tissue.     

Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.     

Normal and aberrant Mesocestoides tetrathyridia from Crocidura spp. (Soricimorpha) in Corsica and Spain

Tetrathyridia of Mesocestoides sp. were collected from the body cavities of the shrews (Insectivora), Crocidura russula, in Valencia, Spain and Crocidura suaveolens on the Mediterranean island of Corsica, France. Specimens were processed by routine microscopic and histological techniques, including examination with brightfield, phase-contrast, and differential-interference-contrast optics. Most tetrathyridia were clustered together inside host-derived fibrotic capsules, but some occurred free in the body cavity. All specimens examined from both locations had solid hindbodies, i.e., lacking a primary lacuna, thus conforming to the plerocercoid metacestode type; all possessed a single normal tetra-acetabulate scolex. All metacestodes from C. russula in Valencia were normal tetrathyridia. Those from C. suaveolens in Corsica were either normal tetrathyridia or had aberrant deep convolutions of an unusually elongated hindbody. No tetrathyridium from either location or host showed tegumental or excretory duct anomalies such as those reported by several authors from aberrant tetrathyridia and spargana in some other locations. No definitive evidence of asexual proliferation was visible in any of the tetrathyridia, but those with abnormally convoluted hindbodies from a single C. suaveolens in Corsica suggest the potential for asexuality by fission of the hindbody. These results add to our understanding of morphological and developmental variation among metacestodes in this widespread and variable genus.     

Elevated insulin sensitivity and β-cell function during pregnancy in mothers of growth-restricted newborns

The "Barker hypothesis" suggests that low birth weight might predict future risk of developing obesity, cardiovascular disease, and type 2 diabetes. Identification of the causes of fetal growth restriction (FGR) is critical for preventive and management strategies. Some studies indicate that maternal carbohydrate metabolism might be involved in FGR development. We aimed to evaluate, in a large number of normotensive pregnant women with normal glucose tolerance, the effect of insulin sensitivity and β-cell function on unexplained fetal growth. A total of 1,814 Caucasian pregnant women with normal prepregnancy body mass index were tested with a 75-g, 2-h glucose load (24-28 gestation wk). Insulin sensitivity was evaluated with fasting (QUICKI) and dynamic index (OGIS) and β-cell function with a modified insulinogenic index as ΔAUC(insulin)/ΔAUC(glucose) and disposition index. FGR was a birth weight below the 5th percentile for gestational age. FGR developed in 99 (5.5%) pregnant women that showed significantly higher QUICKI, OGIS, insulinogenic, and disposition index with respect to women with normal-weight babies (P < 0.0001). By using multiple regression analysis in the FRG group, QUICKI and OGIS appeared as significant independent variables (P < 0.0001 and P < 0.0366, respectively). We conclude that elevated insulin sensitivity seems to be one of the factors involved in determining unexplained fetal growth retardation; its assessment, even only in the fasting state, could be useful to guide any possible monitoring and therapeutic strategies to reduce fetal complications.     

Nickel(II) 2,6-diacetylpyridine bis(isonicotinoylhydrazonate) and bis(benzoylhydrazonate) complexes: structure and antimycobacterial evaluation. Part XI

The reaction of 2,6-diacetylpyridine (dap) and isonicotinoyl- or benzoylhydrazide leads to bishydrazones H(2)dapin (1a) and H(2)dapb (1b), respectively. The condensation can either take place as a bimolecular kinetic process between the two reactants or as a monomolecular metal-templated synthesis in the presence of nickel(II) ions. In the latter case the reaction products are charged 2,6-diacetylpyridine bis(hydrazone) nickel(II) complexes, which can be easily deprotonated to neutral hydrazonates. Diffractometric analysis of one of these [Ni(dapb)](2) (8b) has shown a binuclear structure with two octahedral nickel(II) ions bridged by two helicoidal dap (bishydrazonates) in a spheroidal structure of C(2V) symmetry. The synthesized complexes 8 are promising as antimycobacterial agents against M. tuberculosis H37Rv. In particular, 8b displays significant activity (MIC=0.025 microg/mL) 10-fold higher than rifampin and equal to isoniazid, while its ligand is ineffective. Compound 8b is also capable of reducing HIV-induced cytopathogenic effect in human T(4 )lymphocytes.     

Why does SOD overexpression sometimes enhance,sometimes decrease,hydrogen peroxide production? A minimalist explanation

Toxic effects of superoxide dismutase (SOD) overexpression are commonly attributed to increased hydrogen peroxide (H₂O₂) production. Still, published experiments yield contradictory evidence on whether SOD overexpression increases or decreases H₂O₂ production. We analyzed this issue using a minimal mathematical model. The most relevant mechanisms of superoxide consumption are treated as pseudo first-order processes, and both superoxide production and the activity of enzymes other than SOD were considered constant. Even within this simple framework, SOD overexpression may increase, hold constant, or decrease H₂O₂ production. At normal SOD levels, the outcome depends on the ratio between the rate of processes that consume superoxide without forming H₂O₂ and the rate of processes that consume superoxide with high (≥ 1) H₂O₂ yield. In cells or cellular compartments where this ratio is exceptionally low (< 1), a modest decrease in H₂O₂ production upon SOD overexpression is expected. Where the ratio is higher than unity, H₂O₂ production should increase, but at most linearly, with SOD activity. The results are consistent with the available experimental observations. According to the minimal model, only where most superoxide is eliminated through H₂O₂-free processes does SOD activity have the moderately large influence on H₂O₂ production observed in some experiments.     

First records and potential palaeoecological significance of Dianella (Xanthorrhoeaceae), an extinct representative of the native flora of Rapa Nui (Easter Island)

Easter Island, a remote island in the Pacific Ocean, is currently primarily covered by grasslands, but palaeoecological studies have shown the former presence of different vegetation. Much of its original biota has been removed during the last two millennia, most likely by human activities, and little is known about the native flora. Macrofossil and pollen analyses of a sediment core from the Raraku crater lake have revealed the occurrence of a plant that is currently extinct from the island: Dianella cf. intermedia/adenanthera (Xanthorrhoeaceae), which grew and disappeared at the Raraku site long before human arrival. The occurrence of Dianella within the Raraku sedimentary sequence (between 9.4 and 5.4 cal. kyr b.p.) could have been linked to the existence of favorable palaeoenvironmental conditions (peatland rather than the present-day lacustrine environment) during the early to mid Holocene. This finding contributes new knowledge about indigenous plant diversity on Easter Island and reinforces the usefulness of further macrofossil and pollen analyses to identify native species on Easter Island and elsewhere.     

Human recombinant domain antibodies against multiple sclerosis antigenic peptide CSF114(Glc)

Multiple sclerosis (MS) is a chronic auto‐immune disease characterized by a damage to the myelin component of the central nervous system. Self‐antigens created by aberrant glycosylation have been described to be a key component in the formation of auto‐antibodies. CSF114(Glc) is a synthetic glucopeptide detecting in vitro MS‐specific auto‐antibodies, and it is actively used in diagnostics and research to monitor and quantify MS‐associated Ig levels. We reasoned that antibodies raised against this probe could have been relevant for MS. We therefore screened a human Domain Antibody library against CSF114(Glc) using magnetic separation as a panning method. We obtained and described several clones, and the one with the highest signals was produced as a 6×His‐tagged protein to properly study the binding properties as a soluble antibody. By surface plasmon resonance measurements, we evidenced that our clone recognized CSF114(Glc) with high affinity and specific for the glucosylated peptide. Kinetic parameters of peptide–clone interaction were calculated obtaining a value of K_D in the nanomolar range. Harboring a human framework, this antibody should be very well tolerated by human immune system and may represent a valuable tool for MS diagnosis and therapy, paving the way to new research strategies. Copyright © 2014 John Wiley & Sons, Ltd.