Universidad Autonoma Del Estado De Morelos

Inflammation participates in the development and progression of chronic diseases such as diabetes, cancer, and neurodegenerative disorders. Therefore, the search for novel anti-inflammatory agents is always required. Herein, we report a series of methoxylated 3,4-diarylpyrazoles with potent anti-inflammatory activity in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced topical edema. Most derivatives reduced phorbol's toxicity by more than 50%. The anti-inflammatory activity of the trimethoxylated analog 3r reached 90% inhibition and surpassed that of celecoxib. 3r also reduced the secretion of myeloperoxidase (MPO) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Micrographs of the ear's tissue clearly showed a decrease in thickness and infiltration of neutrophils, which correlates with the reduction of MPO and cytokines. Finally, molecular docking suggested that the series could inhibit cyclooxygenases and displayed a binding mode like that of celecoxib, though the enzymatic assay will be performed in future work.

Growth faltering is prevalent in 96% of children with Phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG). Published long-term growth data is extremely limited. Growth and weight patterns of PMM2-CDG children differ from the general population limiting the utility of existing normative growth charts to track development trajectory in comparison to peers with PMM2-CDG.

Create PMM2-CDG disease-specific height-, weight-, and BMI-for-age reference growth charts (0-20 years).

De-identified growth data was provided by Frontiers in Congenital Disorders of Glycosylation Consortium, CDG Care, Minnesota Partnership for Biotechnology and Medical Genomics, and Glycomine, Inc. Semi-parametric modeling techniques were used to develop PMM2-CDG-specific charts along with nodal-point analyses for quantifying and examining PMM2-CDG growth differences relative to Centers for Disease Control (CDC) reference using one-sided quantile tests.

Data of 156 children (females n = 75) with PMM2-CDG from 1614 visits were used to create height-, weight- and BMI-for-age growth curves. Median follow-up was 8.5 years (SD 4.5) for females and 6.8 years (SD 4.4) for males. CDG females were 13 cm shorter than their CDC reference peers at 20 years (150 vs 163 cm), and males were 16 cm shorter (160 vs 176 cm). All weight and height nodal points were significantly different (p < 0.05) at each age (4, 8, 12, 16, 20 years).

PMM2-CDG specific reference charts can help enable the detection of deviations from peer growth patterns, aid in early detection of coexisting endocrinopathies, help guide treatment decisions and evaluate the effectiveness of new disease-modifying treatments in clinical trials.

Tubulinopathies are a recently characterized group of neurological disorders caused by mutations in tubulin-encoding genes. Among them, mutations in TUBB4A have been linked to hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). In individuals affected by this condition - as well as in the taiep rat, a well-established spontaneous model of the disease - oligodendrocytes display an unusual pattern in both the amount and organization of their microtubules. These anomalies, likely reflecting disrupted microtubule dynamics, are closely tied to cellular dysfunction. However, the precise molecular events driving these changes are still not fully understood. In this study, we investigated whether specific post-translational modifications (PTMs) of tubulin are altered in H-ABC by performing immunostaining on the cerebellum and corpus callosum of control and taiep rats. Compared to controls, taiep rats displayed significantly elevated levels of tubulin acetylation and detyrosination within white matter regions. Moreover, tubulin phosphorylation-typically associated with polymerized tubulin-was also altered and elevated in the taiep model. Notably, increased tubulin acetylation was observed in cells positive for oligodendrocyte markers. Molecular models of this tubulin isotype, both wild type and the A302T mutation, with and without PTMs, suggest new interactions between T302 and the phosphorylated S172 that could account for increased stability. These findings suggest a link between H-ABC and greater microtubule stability in oligodendrocytes, a change that may limit their ability to properly myelinate axons and, in turn, contribute to the disease's characteristic pathology.