Nigella sativa (Black Cumin) Seed Extract Alleviates Symptoms of Allergic Diarrhea in Mice, Involving Opioid Receptors

The incidence of food hypersensitivity and food allergies is on the rise and new treatment approaches are needed. We investigated whether N. sativa, one of its components, thymoquinone, or synthetic opioid receptor (OR)-agonists can alleviate food allergy. Hence, ovalbumin (OVA) -sensitized BALB/c-mice were pre-treated either with a hexanic N. sativa seed extract, thymoquinone, kappa- (U50'4889) or mu-OR-agonists (DAMGO) and subsequently challenged intra-gastrically with OVA. All 4 treatments significantly decreased clinical scores of OVA-induced diarrhea. N. sativa seed extract, thymoquinone, and U50'488 also decreased intestinal mast cell numbers and plasma mouse mast cell protease-1 (MMCP-1). DAMGO, in contrast, had no effect on mast cell parameters but decreased IFNγ, IL-4, IL-5, and IL-10 concentration after ex vivo re-stimulation of mesenteric lymphocytes. The effects on allergy symptoms were reversible by OR-antagonist pre-treatment, whereas most of the effects on immunological parameter were not. We demonstrate that N. sativa seed extract significantly improves symptoms and immune parameters in murine OVA-induced allergic diarrhea; this effect is at least partially mediated by thymoquinone. ORs may also be involved and could be a new target for intestinal allergy symptom alleviation. N. sativa seed extract seems to be a promising candidate for nutritional interventions in humans with food allergy

The nuclear receptor LXR modulates interleukin-18 levels through multiple mechanisms

IL-18 is a member of the IL-1 family involved in innate immunity and inflammation. Deregulated levels of IL-18 are involved in the pathogenesis of multiple disorders including inflammatory and metabolic diseases, yet relatively little is known regarding its regulation. Liver X receptors or LXRs are key modulators of macrophage cholesterol homeostasis and immune responses. Here we show that LXR ligands negatively regulate LPS-induced mRNA and protein expression of IL-18 in bone marrow-derived macrophages. Consistent with this being an LXR-mediated process, inhibition is abolished in the presence of a specific LXR antagonist and in LXR-deficient macrophages. Additionally, IL-18 processing of its precursor inactive form to its bioactive state is inhibited by LXR through negative regulation of both pro-caspase 1 expression and activation. Finally, LXR ligands further modulate IL-18 levels by inducing the expression of IL-18BP, a potent endogenous inhibitor of IL-18. This regulation occurs via the transcription factor IRF8, thus identifying IL-18BP as a novel LXR and IRF8 target gene. In conclusion, LXR activation inhibits IL-18 production through regulation of its transcription and maturation into an active pro-inflammatory cytokine. This novel regulation of IL-18 by LXR could be applied to modulate the severity of IL-18 driven metabolic and inflammatory disorders

Donated chemical probes for open science.

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project

Regulatory regions of the paraoxonase 1 (PON1) gene are associated with neovascular age-related macular degeneration (AMD)

Physiological stress response and oxidative damage are factors for aging processes and, as such, are thought to contribute to neovascular age-related macular degeneration (AMD). Paraoxonase 1 (PON1) is an enzyme that plays an important role in oxidative stress and aging. We investigated association of DNA sequence variants (SNP) within the upstream regulatory region of the PON1 gene with neovascular AMD in 305 patients and 288 controls. Four of the seven tested SNPs (rs705379, rs705381, rs854573, and rs757158) were more frequently found in AMD patients compared to controls (P = 0.0099, 0.0295, 0.0121, and 0.0256, respectively), and all but one (SNP rs757158) are in linkage disequilibrium. Furthermore, haplotype TGGCCTC conferred protection (odds ratio (OR) = 0.76, (CI) = 0.60-0.97) as it was more frequently found in control individuals, while haplotype CGATGCT increased the risk (OR = 1.55, CI = 1.09-2.21) for AMD. These results were also reflected when haplotypes for the untranscribed and the 5'untranslated regions (5'UTR) were analyzed separately. To assess haplotype correlation with levels of gene expression, the three SNPs within the 5'UTR were tested in a luciferase reporter assay. In retinal pigment epithelium-derived ARPE19 cells, we were able to measure significant differences in reporter levels, while this was not observed in kidney-derived HEK293 cells. The presence of the risk allele A (SNP rs705381) caused an increase in luciferase activity of approximately twofold. Our data support the view that inflammatory reactions mediated through anti-oxidative activity may be relevant to neovascular age-related macular degeneration

Impact of physical fitness and biometric data on the quality of external chest compression: a randomised, crossover trial

<p>Abstract</p> <p>Background</p> <p>During circulatory arrest, effective external chest compression (ECC) is a key element for patient survival. In 2005, international emergency medical organisations changed their recommended compression-ventilation ratio (CVR) from 15:2 to 30:2 to acknowledge the vital importance of ECC. We hypothesised that physical fitness, biometric data and gender can influence the quality of ECC. Furthermore, we aimed to determine objective parameters of physical fitness that can reliably predict the quality of ECC.</p> <p>Methods</p> <p>The physical fitness of 30 male and 10 female healthcare professionals was assessed by cycling and rowing ergometry (focussing on lower and upper body, respectively). During ergometry, continuous breath-by-breath ergospirometric measurements and heart rate (HR) were recorded. All participants performed two nine-minute sequences of ECC on a manikin using CVRs of 30:2 and 15:2. We measured the compression and <it>de</it>compression depths, compression rates and assessed the participants' perception of exhaustion and comfort. The median body mass index (BMI; male 25.4 kg/m²and female 20.4 kg/m²) was used as the threshold for subgroup analyses of participants with higher and lower BMI.</p> <p>Results</p> <p>HR during rowing ergometry at 75 watts (HR₇₅) correlated best with the quality of ECC (<it>r </it>= -0.57, <it>p </it>< 0.05). Participants with a higher BMI and better physical fitness performed better and showed less fatigue during ECC. These results are valid for the entire cohort, as well as for the gender-based subgroups. The compressions of female participants were too shallow and more rapid (mean compression depth was 32 mm and rate was 117/min with a CVR of 30:2). For participants with a lower BMI and higher HR₇₅, the compression depth decreased over time, beginning after four minutes for the 15:2 CVR and after three minutes for the 30:2 CVR. Although found to be more exhausting, a CVR of 30:2 was rated as being more comfortable.</p> <p>Conclusion</p> <p>The quality of the ECC and fatigue can both be predicted by BMI and physical fitness. An evaluation focussing on the upper body may be a more valid predictor of ECC quality than cycling based tests. Our data strongly support the recommendation to relieve ECC providers after two minutes.</p

Improving M cell mediated transport across mucosal barriers: do certain bacteria hold the keys?

Specialized microfold (M) cells of the follicle-associated epithelium (FAE) of the mucosal-associated lymphoid tissue (MALT) in gut and the respiratory system play an important role in the genesis of both mucosal and systemic immune responses by delivering antigenic substrate to the underlying lymphoid tissue where immune responses start. Although it has been shown that dendritic cells (DC) also have the ability to sample antigens directly from the gut lumen, M cells certainly remain the most important antigen-sampling cell to be investigated in order to devise novel methods to improve mucosal delivery of biologically active compounds. Recently, novel information on the interactions between bacteria and FAE have come to light that unveil further the complex cross-talk taking place at mucosal interfaces between bacteria, epithelial cells and the immune system and which are central to the formation and function of M cells. In particular, it has been shown that M cell mediated transport of antigen across the FAE is improved rapidly by exposure to certain bacteria, thus opening the way to identify new means to achieve a more effective mucosal delivery. Here, these novel findings and their potential in mucosal immunity are analysed and discussed, and new approaches to improve antigen delivery to the mucosal immune system are also proposed