A de novo YY1 missense variant expanding the Gabriele-de Vries syndrome phenotype and affecting X-chromosome inactivation.

Yin and Yang 1 gene (YY1; MIM#600,013) is recognized as a dual transcriptional activating and repressing factor, RNA-binding protein, and 3D chromatin regulator, with multi roles in neurodevelopmental and maintenance pathways. YY1 haploinsufficiency caused either by heterozygous sequence variants or deletions involving the whole gene has been recently associated with Gabriele-de Vries syndrome (GADEVS), a rare congenital autosomal dominant condition, leading to intellectual disability (ID) and multiple physical/behavioural abnormalities. Herein, we describe clinical and molecular findings from a Brazilian female harbouring a de novo missense pathogenic variant in YY1 gene (NM_003403.5:c.1106A > G; p.Asn369Ser) found by whole exome sequencing with potential implications for protein structure and function. Undescribed or uncommon clinical features in this patient included non-febrile seizures, severe scoliosis, hearing impairment, and chorioretinitis. Further bioinformatics analyses using YY1-other protein interaction networks reinforced the involvement of YY1 interactors in such phenotypes, in exception of chorioretinitis. Moreover, X-chromosome inactivation (XCI) skewing was evidenced in the patient and attributed to the haploinsufficiency of YY1, which direct and indirectly interacts with numerous XCI key regulators. Besides expanding the mutational and phenotype spectrum of GADEVS, our results highlight the role of YY1 as an essential autosomal regulator of XCI epigenetic process.

The Protective Potential of Phyllanthus niruri and Corilagin on Gastric Lesions Induced in Rodents by Different Harmful Agents.

The gastroprotective effect of the methanol extract of Phyllantus niruri and its main constituent, corilagin, were studied in vivo. The extract (50, 125, or 250 mg/kg, p. o.) inhibited ethanol-induced lesions in rats by 43 % (p < 0.001), 69 % (p < 0.001), and 99 % (p < 0.001), respectively. It also inhibited the formation of indomethacin-induced gastric ulcers in rats by 80 % (p < 0.01), 89 % (p < 0.01), and 97 % (p < 0.01). A decrease in lipid hydroperoxide levels (p < 0.01) and in myeloperoxidase activity (p < 0.05) evidenced a reduction of oxidative damage and neutrophil infiltration in gastric tissues from ulcerated mice using ethanol/HCl. Potent in vitro free radical scavenger activity (IC50 = 0.07) using the DPPH assay was observed. In contrast, the extract (250 mg/kg, i. d.) did not show antisecretory activity in pylorus-ligated rats, and also failed to inhibit the H+,K+-ATPase activity in vitro. However, in pylorus-ligated rats, the extract (50, 125, and 250 mg/kg, i. d.) increased adhered mucus content by 22 % (p < 0.05), 28 % (p < 0.01), and 38 % (p < 0.01), respectively. The involvement of prostaglandins, nonprotein endogenous sulfhydryl compounds, α2-receptors, and endogenous nitric oxide in the gastroprotection elicited by the extract was also evaluated. Finally, corilagin reduced the lesion area of ethanol-induced gastric ulcers in mice by 88 % (30 mg/kg, p. o.; p < 0.001). Based on these results, it has been concluded that P. niruri methanol extract possesses gastroprotective activity by different and complementary pathways, which together promote an improvement in gastric cytoprotection. The presence of corilagin may partially explain the effectiveness of the extract against gastric damage.

Role of gastric mucus secretion, oxinitrergic system and sulfhydryl groups on the gastroprotection elicited by Polygala cyparissias (Polygalaceae) in mice.

OBJECTIVES: This study has aimed to assess the mechanisms of action for the gastroprotective effect of the acetone extract (PCAE) and methanol fraction (PCMF) of Polygala cyparissias, as well as to evaluate the activity of 1,3,6,8-tetrahydroxy-2,7-dimethoxyxanthone (1), 1,7-dihydroxy-2,3-dimethoxyxanthone (2) and astragalin (3). METHODS: Gastric secretion and mucus content were determined by pylorus ligation in mice. Nitric oxide (NO) and sulfhydryl group participation were observed by the pretreatment of mice with L-NAME or NEM. Acute ulcer was induced by ethanol/HCl and chronic ulcer by acetic acid. Anti-Helicobacter pylori activity was evaluated by the agar solid dilution assay. KEY FINDINGS: Neither PCAE nor PCMF had the ability to reduce H(+) concentration. However, both of them enhanced mucus secretion. PCAE demonstrated its gastroprotection in a NO-dependent manner, while PCMF exerted the activity depending on the sulfhydryl group. In chronic ulcer, the curative ratios for the PCAE and PCMF were 67.5 and 58.4%, respectively. No effect over H. pylori was detected. Compounds 1, 2 and 3 were able to reduce lesions in the order of 79.6, 73.8 and 67.6%, respectively. CONCLUSIONS: The data suggested that PCAE and PCMF displayed antiulcer activity due to different mechanisms and with the participation of phenolic compounds obtained from the plant.