Evaluation of the anti-inflammatory effects of synthesised tanshinone I and isotanshinone I analogues in zebrafish

During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds

Detection of genetic incompatibilities in non-model systems using simple genetic markers: hybrid breakdown in the haplodiploid spider mite Tetranychus evansi

When two related species interbreed, their hybrid offspring frequently suffer from reduced fitness. The genetics of hybrid incompatibility are described by the Bateson–Dobzhansky–Muller (BDM) model, where fitness is reduced by epistatic interactions between alleles of heterospecific origin. Unfortunately, most empirical evidence for the BDM model comes from a few well-studied model organisms, restricting our genetic understanding of hybrid incompatibilities to limited taxa. These systems are predominantly diploid and incompatibility is often complete, which complicates the detection of recessive allelic interactions and excludes the possibility to study viable or intermediate stages. Here, we advocate research into non-model organisms with haploid or haplodiploid reproductive systems and incomplete hybrid incompatibility because (1) dominance is absent in haploids and (2) incomplete incompatibility allows comparing affected with unaffected individuals. We describe a novel two-locus statistic specifying the frequency of individuals for which two alleles co-occur. This approach to studying BDM incompatibilities requires genotypic characterization of hybrid individuals, but not genetic mapping or genome sequencing. To illustrate our approach, we investigated genetic causes for hybrid incompatibility between differentiated lineages of the haplodiploid spider mite Tetranychus evansi, and show that strong, but incomplete, hybrid breakdown occurs. In addition, by comparing the genotypes of viable hybrid males and inviable hybrid male eggs for eight microsatellite loci, we show that nuclear and cytonuclear BDM interactions constitute the basis of hybrid incompatibility in this species. Our approach opens up possibilities to study BDM interactions in non-model taxa, and may give further insight into the genetic mechanisms behind hybrid incompatibility