Structure and reactivity of [RuII(terpy)(N^N)Cl]Cl complexes: consequences for biological applications

The crystal structures of [RuII(terpy)(bipy)Cl]Cl·2H2O and [RuII(terpy)(en)Cl]Cl·3H2O, where terpy = 2,2′:6′,2′′-terpyridine, bipy = 2,2′-bipyridine and en = ethylenediamine, were determined and compared to the structure of the complexes in solution obtained by multi-nuclear NMR spectroscopy in DMSOd-6 as a solvent. In aqueous solution, both chlorido complexes aquate fully to the corresponding aqua complexes, viz. [RuII(terpy)(bipy)(H2O)]2+ and [RuII(terpy)(en)(H2O)]2+, within ca. 2 h and ca. 2 min at 37 °C, respectively. The spontaneous aquation reactions can only be suppressed by chloride concentrations as high as 2 to 4 M, i.e. concentrations much higher than that found in human blood. The corresponding aqua complexes are characterized by pKa values of ca. 10 and 11, respectively, which suggest a more labile coordinated water molecule in the case of the [RuII(terpy)(en)(H2O)]2+ complex. Substitution reactions of the aqua complexes with chloride, cyanide and thiourea show that the [RuII(terpy)(en)(H2O)]2+ complex is 30-60 times more labile than the [RuII(terpy)(bipy)(H2O)]2+ complex at 25 °C. Water exchange reactions for both complexes were studied by 17O-NMR and DFT calculations (B3LYP(CPCM)/def2tzvp//B3LYP/def2svp and ωB97XD(CPCM)/def2tzvp//B3LYP/def2svp). Thermal and pressure activation parameters for the water exchange and ligand substitution reactions support the operation of an associative interchange (Ia) process. The difference in reactivity between these complexes can be accounted for in terms of π-back bonding effects of the terpy and bipy ligands and steric hindrance on the bipy complex. Consequences for eventual biological application of the chlorido complexes are discussed

Impaired Abcb1a function and red meat in a translational colitis mouse model induces inflammation and alters microbiota composition

Inflammatory Bowel Disease (IBD) affects approximately 0.3% of the global population, with incidence rates rising dramatically worldwide. Emerging evidence points to an interplay between exposome factors such as diet and gut microbiota, host genetics, and the immune system as crucial elements in IBD development. ATP-binding cassette (ABC) transporters, including human p-glycoprotein encoded by the Abcb1 gene, influence intestinal inflammation, and their expression may interact with environmental factors such as diet and gut microbes. Our study aimed to examine the impact of protein sources on a genetic colitis mouse model. Methods Abcb1a-deficient colitis mice were fed either casein or red meat-supplemented diets to investigate potential colitis-aggravating components in red meat and their effects on host-microbiota interactions. We conducted deep label free quantitative proteomic inflammation profiling of gastrointestinal tissue (colon, ileum) and urine, and determined the overall microbiome in feces using 16S rRNA gene sequencing. Results A quantitative discovery based proteomic analysis of intestinal tissue and urine revealed associations between ileum and urine proteomes in relation to Abcb1a deficiency. The absence of Abcb1a efflux pump function and diet-induced intestinal inflammation impacted multiple systemic immune processes, including extensive neutrophil extracellular trap (NET) components observed in relation to neutrophil degranulation throughout the gastrointestinal tract. Conclusion Insights into dysregulated biological pathways in this disease model might offer translational biomarkers based on NETs and improved understanding of IBD pathogenesis in human patients. Our findings demonstrate that drug transporter deficiency induces substantial changes in the microbiota, leading to increased levels of IBD-associated strains and resulting in intestinal inflammation. GRAPHICAL ABSTRACT

Impaired Abcb1a function and red meat in a translational colitis mouse model induces inflammation and alters microbiota composition

Inflammatory Bowel Disease (IBD) affects approximately 0.3% of the global population, with incidence rates rising dramatically worldwide. Emerging evidence points to an interplay between exposome factors such as diet and gut microbiota, host genetics, and the immune system as crucial elements in IBD development. ATP-binding cassette (ABC) transporters, including human p-glycoprotein encoded by the Abcb1 gene, influence intestinal inflammation, and their expression may interact with environmental factors such as diet and gut microbes. Our study aimed to examine the impact of protein sources on a genetic colitis mouse model.MethodsAbcb1a-deficient colitis mice were fed either casein or red meat-supplemented diets to investigate potential colitis-aggravating components in red meat and their effects on host-microbiota interactions. We conducted deep label free quantitative proteomic inflammation profiling of gastrointestinal tissue (colon, ileum) and urine, and determined the overall microbiome in feces using 16S rRNA gene sequencing. Microbiota shifts by diet and protein transporter impairment were addressed by multivariate statistical analysis. Colon and systemic gut inflammation were validated through histology and immune assays, respectively.ResultsA quantitative discovery based proteomic analysis of intestinal tissue and urine revealed associations between ileum and urine proteomes in relation to Abcb1a deficiency. The absence of Abcb1a efflux pump function and diet-induced intestinal inflammation impacted multiple systemic immune processes, including extensive neutrophil extracellular trap (NET) components observed in relation to neutrophil degranulation throughout the gastrointestinal tract. The colitis model’s microbiome differed significantly from that of wild-type mice, indicating the substantial influence of efflux transporter deficiency on microbiota.ConclusionThe proteomic and microbiota analyzes of a well-established murine model enabled the correlation of gastrointestinal interactions not readily identifiable in human cohorts. Insights into dysregulated biological pathways in this disease model might offer translational biomarkers based on NETs and improved understanding of IBD pathogenesis in human patients. Our findings demonstrate that drug transporter deficiency induces substantial changes in the microbiota, leading to increased levels of IBD-associated strains and resulting in intestinal inflammation.GRAPHICAL ABSTRAC

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Direct evidence for the catalase activity of [RuV(edta)(O)]−[Ru^V(edta)(O)]^-

Reported is the first example of a ruthenium(III) complex, RuIII(edta) (edta4− = ethylenediaminetetraacetate), that catalyzes the disproportion of H2O2 to O2 and water in resemblance to catalase activity, and shedding light on the possible mechanism of action of the [RuV(edta)(O)]− formed in the reacting system

RuIII(edta) mediated oxidation of azide in the presence of hydrogen peroxide. Azide versus peroxide activation

The [RuIII(edta)(H2O)]− (edta4− = ethylenediaminetetraacetate) complex catalyzes the oxidation of azide (N3−) with H2O2, mimicking the action of metallo-enzymes such as catalase and peroxidase in biochemistry. The kinetics of the catalytic oxidation process was studied by using stopped-flow and rapid-scan spectrophotometry as a function of [RuIII(edta)], [H2O2], [N3−] and pH. The catalytic activity of the different oxidizing species produced in the reaction of [RuIII(edta)(H2O)]− with H2O2 for the oxidation of azide was compared to the oxidation of coordinated azide in [RuIII(edta)N3]2− by H2O2. Detailed reaction mechanisms in agreement with the spectroscopic and kinetic data are presented for both reaction paths