97 research outputs found

    Intravenous injection of cyclosporin A loaded lipid nanocapsules fights inflammation and immune system activation in a mouse model of diabetic retinopathy

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    Inflammation and immune system activation are key pathologic events in the onset and escalation of diabetic retinopathy (DR). Both are driven by cytokines and complement originating from the retinal pigment epithelium (RPE). Despite the RPE’s pivotal role, there is no therapeutic tool to specifically interfere with the RPE-related pathomechanism. A therapy that addresses RPE cells and counteracts inflammation and immune response would be of paramount value for the early treatment of DR, where currently are no specific therapies available. Here, we utilized lipoprotein-mimetic lipid nanocapsules to deliver the anti-inflammatory and immunosuppressive drug cyclosporin A (CsA) to RPE cells. Using a mouse model of DR that mirrors all pathologic aspects of human DR, we demonstrate that intravenously applied CsA-loaded lipid nanocapsules comprehensively counteract inflammation and immune system activation. One single injection suppressed the expression of pro-inflammatory cytokines, dampened macrophage infiltration, and prevented macrophage and microglia activation in eyes with DR. This work shows that CsA-loaded lipid nanocapsules can offer new avenues for the treatment of DR

    A single intravenous injection of cyclosporin A–loaded lipid nanocapsules prevents retinopathy of prematurity

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    Retinopathy of prematurity (ROP) is a retinal disease that threatens the vision of prematurely born infants. Severe visual impairment up to complete blindness is caused by neovascularization and inflammation, progressively destroying the immature retina. ROP primarily affects newborns in middle- and low-income countries with limited access to current standard treatments such as intraocular drug injections and laser- or cryotherapy. To overcome these limitations, we developed a nanotherapeutic that effectively prevents ROP development with one simple intravenous injection. Its lipid nanocapsules transport the antiangiogenic and anti-inflammatory cyclosporin A efficiently into disease-driving retinal pigment epithelium cells. In a mouse model of ROP, a single intravenous injection of the nanotherapeutic prevented ROP and led to normal retinal development by counteracting neovascularization and inflammation. This nanotherapeutic approach has the potential to bring about a change of paradigm in ROP therapy and prevent millions of preterm born infants from developing ROP

    Gut contents, digestive half-lives and feeding state prediction in the soil predatory mite Pergamasus longicornis (Mesostigmata: Parasitidae)

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    Mid- and hind-gut lumenal changes are described in the free-living predatory soil mite Pergamasus longicornis (Berlese) from a time series of histological sections scored during and after feeding on fly larval prey. Three distinct types of tangible material are found in the lumen. Bayesian estimation of the change points in the states of the gut lumenal contents over time is made using a time-homogenous first order Markov model. Exponential processes within the gut exhibit ’stiff’ dynamics. A lumen is present throughout the midgut from 5 min after the start of feeding as the gut rapidly expands. It peaks at about 21.5 h - 1.5 days and persists post-feeding (even when the gut is contracted) up until fasting/starvation commences 10 days post start of feeding. The disappearance of the lumen commences 144 h after the start of feeding. Complete disappearance of the gut lumen make take 5-9 weeks from feeding commencing. Clear watery prey material arrives up to 10 min from the start of feeding - driving gut lumen expansion. Intracellular digestion triggered by maximum gut expansion is indicated. Detectable granular prey material appears in the lumen during the concentrative phase of coxal droplet production and, despite a noticeable collapse around 12 h, lasts in part for 52.5 h. Posterior midgut regions differ slightly from anterior regions in their main prey food dynamics being somewhat faster in processing yet being slightly delayed. Posterior regions are confirmed as Last-In-Last-Out depots, anterior regions confirmed as First-In-First-Out conveyor belt processes. Evidence for differential lability of prey fractions is found. A scheme of granular imbibed prey material being first initially rapidly absorbed (t andfrac12; = 23 min), and also being quickly partly converted to globular material extra-corporeally/extracellularly (t andfrac12; = 36 min) - which then rapidly disappears (t andfrac12; =1.1 h, from a peak around 4 h) is presented. This is then followed by slow intracellular digestion (t andfrac12; = 6.9 h) of the resultant resistant prey residue matching the slow rate of appearance of opaque pre-excretory egestive refractive grains (overall t andfrac12; = 4.5 days). The latter confirmed latent ’catabolic fraction’ (along with Malpighian tubule produced guanine crystals) drives rectal vesicle expansion as ’faeces’ during the later phases of gut emptying/contraction. Catabolic half-lives are of the order of 6.3-7.8 h. Membraneous material is only present in the lumen of the gut in starving mites. No obvious peritrophic membrane was observed. The total feeding cycle time may be slightly over 52.5 h. Full clearance in the gut system of a single meal including egestive and excretory products may take up to 3 weeks. Independent corroborative photographs are included and with posterior predictive densities confirm the physiological sequence of:- ingestion/digestion; egestion; excretion; defecation; together with their timings. Visually dark midguts almost certainly indicate egestive refractive grains (?xanthine) production. Nomograms to diagnose the feeding state of P.longicornis in field samples are presented and show that the timing of these 4 phases in the wild could be inferred by scoring 10-12 mites out of a sample of 20. Suggestions to critically confirm or refute the conclusions are included

    Human cathepsin D.

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    C<sub>4</sub>-like photosynthesis and the effects of leaf senescence on C<sub>4</sub>-like physiology in Sesuvium sesuvioides (Aizoaceae)

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    Sesuvium sesuvioides (Sesuvioideae, Aizoaceae) is a perennial, salt-tolerant herb distributed in flats, depressions, or disturbed habitats of southern Africa and the Cape Verdes. Based on carbon isotope values, it is considered a C4 species, despite a relatively high ratio of mesophyll to bundle sheath cells (2.7:1) in the portulacelloid leaf anatomy. Using leaf anatomy, immunocytochemistry, gas exchange measurements, and enzyme activity assays, we sought to identify the biochemical subtype of C4 photosynthesis used by S. sesuvioides and to explore the anatomical, physiological, and biochemical traits of young, mature, and senescing leaves, with the aim to elucidate the plasticity and possible limitations of the photosynthetic efficiency in this species. Assays indicated that S. sesuvioides employs the NADP-malic enzyme as the major decarboxylating enzyme. The activity of C4 enzymes, however, declined as leaves aged, and the proportion of water storage tissue increased while air space decreased. These changes suggest a functional shift from photosynthesis to water storage in older leaves. Interestingly, S. sesuvioides demonstrated CO2 compensation points ranging between C4 and C3–C4 intermediate values, and immunocytochemistry revealed labeling of the Rubisco large subunit in mesophyll cells. We hypothesize that S. sesuvioides represents a young C4 lineage with C4-like photosynthesis in which C3 and C4 cycles are running simultaneously in the mesophyll

    Intravenous injection of cyclosporin A loaded lipid nanocapsules fights inflammation and immune system activation in a mouse model of diabetic retinopathy

    No full text
    Inflammation and immune system activation are key pathologic events in the onset and escalation of diabetic retinopathy (DR). Both are driven by cytokines and complement originating from the retinal pigment epithelium (RPE). Despite the RPE's pivotal role, there is no therapeutic tool to specifically interfere with the RPE-related pathomechanism. A therapy that addresses RPE cells and counteracts inflammation and immune response would be of paramount value for the early treatment of DR, where currently are no specific therapies available. Here, we utilized lipoprotein-mimetic lipid nanocapsules to deliver the anti-inflammatory and immunosuppressive drug cyclosporin A (CsA) to RPE cells. Using a mouse model of DR that mirrors all pathologic aspects of human DR, we demonstrate that intravenously applied CsA-loaded lipid nanocapsules comprehensively counteract inflammation and immune system activation. One single injection suppressed the expression of pro-inflammatory cytokines, dampened macrophage infiltration, and prevented macrophage and microglia activation in eyes with DR. This work shows that CsA-loaded lipid nanocapsules can offer new avenues for the treatment of DR.ISSN:2190-393XISSN:2190-394
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