Gold Thione Complexes

The reaction of the ligand Et4todit (4,5,6,7-Tetrathiocino-[1,2-b:3,4-b']-diimidazolyl-1,3,8,10-tetraethyl-2,9-dithione) with gold complexes leads to the dinuclear gold(I) complexes [{Au(C6F5)}2(Et4todit)] and [Au(Et4todit)]2(OTf)2, which do not contain any gold-gold interactions, or to the gold(III) derivative [{Au(C6F5)3}2(Et4todit)]. The cristal structures have been established by X-ray diffraction studies and show that the gold centers coordinate to the sulfur atoms of the imidazoline-2-thione groups

miR-369-3p modulates inducible nitric oxide synthase and is involved in regulation of chronic inflammatory response

Dendritic cells are the most important antigen-presenting cells that link the innate and acquired immune system. In our previous study, we identified that the upregulation of miR-369-3p suppresses the LPS-induced inflammatory response, reducing C/EBP-β, TNFα and IL-6 production. With the aim of gaining further insight into the biological function of miR-369-3p during acute inflammatory response, in the present study we identified novel gene targets of miR-369-3p and demonstrated the suppressive ability of these genes on the inflammatory dendritic cells. Bioinformatic analyses revealed that iNOS is a potential target of miR-369-3p. We demonstrated that the ectopic induction of miR-369-3p markedly reduced iNOS mRNA and protein as well as NO production. Moreover, we found that the upregulation of miR-369-3p decreased the release of TNFα, IL-6, IL-12, IL-1α, IL-1β in response to LPS, and increased the production of anti-inflammatory cytokines such as IL-10 and IL-1RA. In addition, LPS-induced nuclear translocation of NF-kB was inhibited by miR-369-3p. Levels of miR-369-3p were decreased in human inflamed regions of human intestine obtained from IBD patients. Our results provide novel additional information on miR-369-3p as a potential core of the signaling regulating the inflammatory response. These findings suggest that miR-369-3p should be considered as a potential target for the future development of new molecular therapeutic approaches

Interleukin-1β blockade reduces intestinal inflammation in a murine model of Tumor Necrosis Factor-independent ulcerative colitis

Background & aimsInflammatory bowel diseases (IBDs) are multifactorial diseases commonly treated with either immunomodulatory drugs or anti-tumor necrosis factor (TNF). Currently, failure to respond to anti-TNF therapy (assessed not prior to 8-12 weeks after starting treatment) occurs in 20-40% of patients enrolled in clinical trials and 10-20% in clinical practice. Murine models of IBD provide important tools to better understand disease mechanism(s). In this context and among the numerous models available, Winnie-TNF-KO mice were recently reported to display characteristics of ulcerative colitis (UC) that are independent of TNF, and with increased IL-1β production.MethodsHerein, the efficacy of recombinant (r) IL-1 receptor antagonist (IL-1Ra, Anakinra) administration was evaluated in Winnie-TNF-KO mice, utilized as an UC model of primary anti-TNF non-responders.ResultsWe analyzed gut mucosal biopsies and circulating cytokine profiles of a cohort of 30 UC patients; approximately 75% of primary non-responders were characterized by abundant IL-1β in both the serum and local intestinal tissues. In Winnie-TNF-KO mice, administration of Anakinra efficiently reduced the histological score of the distal colon, which represents the most common site of inflammation in Winnie mice. Furthermore, among lamina propria and mesenteric lymph node-derived T cells, IFNγ-expressing CD8+ T cells were significantly reduced following Anakinra administration.ConclusionsOur study provides new insight and alternative approaches to treat UC patients, and point to anti-IL-1 strategies (i.e., Anakinra) that may be a more effective therapeutic option for primary non-responders to anti-TNF therapy

Flow Index accurately identifies breaths with low or high inspiratory effort during pressure support ventilation

Background Flow Index, a numerical expression of the shape of the inspiratory flow-time waveform recorded during pressure support ventilation, is associated with patient inspiratory effort. The aim of this study was to assess the accuracy of Flow Index in detecting high or low inspiratory effort during pressure support ventilation and to establish cutoff values for the Flow index to identify these conditions. The secondary aim was to compare the performance of Flow index,of breathing pattern parameters and of airway occlusion pressure (P0.1) in detecting high or low inspiratory effort during pressure support ventilation. Methods Data from 24 subjects was included in the analysis, accounting for a total of 702 breaths. Breaths with high inspiratory effort were defined by a pressure developed by inspiratory muscles (Pmusc) greater than 10 cmH2O while breaths with low inspiratory effort were defined by a Pmusc lower than 5 cmH2O. The areas under the receiver operating characteristic curves of Flow Index and respiratory rate, tidal volume,respiratory rate over tidal volume and P0.1 were analyzed and compared to identify breaths with low or high inspiratory effort. Results Pmusc, P0.1, Pressure Time Product and Flow Index differed between breaths with high, low and intermediate inspiratory effort, while RR, RR/VT and VT/kg of IBW did not differ in a statistically significant way. A Flow index higher than 4.5 identified breaths with high inspiratory effort [AUC 0.89 (CI 95% 0.85–0.93)], a Flow Index lower than 2.6 identified breaths with low inspiratory effort [AUC 0.80 (CI 95% 0.76–0.83)]. Conclusions Flow Index is accurate in detecting high and low spontaneous inspiratory effort during pressure support ventilation

Quercetin exposure suppresses the inflammatory pathway in intestinal organoids from winnie mice

Inflammatory bowel diseases (IBDs) are chronic and relapsing immune disorders that result, or possibly originate, from epithelial barrier defects. Intestinal organoids are a new reliable tool to investigate epithelial response in models of chronic inflammation. We produced organoids from the ulcerative colitis murine model Winnie to explore if the chronic inflammatory features observed in the parental intestine were preserved by the organoids. Furthermore, we investigated if quercetin administration to in vitro cultured organoids could suppress LPS-induced inflammation in wild-type organoids (WT-organoids) and spontaneous inflammation in ulcerative colitis organoids (UC-organoids). Our data demonstrate that small intestinal organoids obtained from Winnie mice retain the chronic intestinal inflammatory features characteristic of the parental tissue. Quercetin administration was able to suppress inflammation both in UC-organoids and in LPS-treated WT-organoids. Altogether, our data demonstrate that UC-organoids are a reliable experimental system for investigating chronic intestinal inflammation and pharmacological responses

Dysbiosis Triggers ACF Development in Genetically Predisposed Subjects

Background: Colorectal cancer (CRC) is the third most common cancer worldwide, characterized by a multifactorial etiology including genetics, lifestyle, and environmental factors including microbiota composition. To address the role of microbial modulation in CRC, we used our recently established mouse model (the Winnie-APCMin/+) combining inflammation and genetics.Methods: Gut microbiota profiling was performed on 8-week-old Winnie-APCMin/+ mice and their littermates by 16S rDNA gene amplicon sequencing. Moreover, to study the impact of dysbiosis induced by the mother's genetics in ACF development, the large intestines of APCMin/+ mice born from wild type mice were investigated by histological analysis at 8 weeks.Results: ACF development in 8-week-old Winnie-APCMin/+mice was triggered by dysbiosis. Specifically, the onset of ACF in genetically predisposed mice may result from dysbiotic signatures in the gastrointestinal tract of the breeders. Additionally, fecal transplant from Winnie donors to APCMin/+ hosts leads to an increased rate of ACF development.Conclusions: The characterization of microbiota profiling supporting CRC development in genetically predisposed mice could help to design therapeutic strategies to prevent dysbiosis. The application of these strategies in mothers during pregnancy and lactation could also reduce the CRC risk in the offspring