Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

An Upgraded, Highly Saturated Linkage Map of Japanese Plum (Prunus salicina Lindl.), and Identification of a New Major Locus Controlling the Flavan-3-ol Composition in Fruits.

Japanese plum fruits are rich in phenolic compounds, such as anthocyanins and flavan-3-ols, whose contents vary significantly among cultivars. Catechin (C) and epicatechin (EC) are flavan-3-ol monomers described in the fruits of this species and are associated with bitterness, astringency, antioxidant capacity, and susceptibility to enzymatic mesocarp browning. In this study, we aimed to identify quantitative trait loci (QTL) associated with the content of flavan-3-ol in Japanese plum fruits. We evaluated the content of C and EC in the mesocarp and exocarp of samples from 79 and 64 seedlings of an F1 progeny (<'98-99' × 'Angeleno'>) in the first and second seasons, respectively. We also constructed improved versions of linkage maps from '98-99' and 'Angeleno,' presently called single-nucleotide polymorphisms (SNPs) after mapping the already available GBS reads to Prunus salicina Lindl. cv. 'Sanyueli' v2.0 reference genome. These data allowed for describing a cluster of QTLs in the cultivar, 'Angeleno,' associated with the flavan-3-ol composition of mesocarp and exocarp, which explain up to 100% of the C/EC ratio. Additionally, we developed a C/EC metabolic marker, which was mapped between the markers with the highest log of odds (LOD) scores detected by the QTL analysis. The C/EC locus was located in the LG1, at an interval spanning 0.70 cM at 108.30-108.90 cM. Our results suggest the presence of a novel major gene controlling the preferential synthesis of C or EC in the Japanese plum fruits. This study is a significant advance in understanding the regulation of synthesizing compounds associated with fruit quality, postharvest, and human health promotion.

Detection of Quantitative Trait Loci Controlling the Content of Phenolic Compounds in an Asian Plum (Prunus salicina L.) F1 Population.

Consumption of fresh fruit is known to protect against non-communicable diseases due to the fruit's content in compounds with an antioxidant capacity, among them is polyphenols. Asian plums (Prunus salicina L.) accumulate more than 40 phenolic compounds, with a remarkable diversity in their profiles, depending on the variety and environmental conditions. Although candidate genes have been indicated to control this trait, the loci controlling its phenotypic variation have not yet been defined in this species. The aim of this work was to identify the quantitative trait Loci (QTL) controlling the phenolic compounds content in the Asian plum skin and flesh. Using UHPLC-DAD-Orbitrap-MS, we determined that cyanidin-3-glucoside and cyanidin-3-rutinoside are the main anthocyanins in Asian plums. Other anthocyanins found to a lesser extent were tentatively identified as cyanidin bound to different sugar and procyanidin moieties. Then we phenotyped fruits of 92 and 80 F1 seedlings from the cross < "98.99" × "Angeleno"> (98 Ang) for two harvest seasons. We used HPLC-DAD to quantify single anthocyanin and spectrophotometric techniques to determine the total content of phenols, flavonoids, procyanidins, and antioxidant activity (DPPH and FRAP). To determine the phenotype-genotype association of phenolic compounds content, phenotypic values (adjusted by linear mixed-effects models), genotypic data and linkage maps were analyzed with the multiple QTL model (MQM) approach. We found a total of 21 significant trait-marker associations: 13 QTLs segregating from "98.99" and 8 QTLs from "Angeleno." From these associations, 8 corresponded to phenolic compound content in the flesh and 13 in the skin. Phenotype variance was explained by the detected loci, ranging from 12.4 to 27.1%. The identified loci are related to the content of cyanidin-3-glucoside (LG4), cyanidin-3-rutinoside (LG4), total flavonoids and procyanidins (LG5 and LG8), and minor anthocyanin compounds (LG3 and LG4). These results will help improve the efficiency of breeding programs for the generation of Asian plum varieties with high phenolic compound content.