Late gestation fetal hypothyroidism alters cell cycle regulation across multiple organ systems.

BACKGROUND: Hypothyroidism is a common endocrine disruption observed in utero that adversely affects fetal growth and maturation leading to long-term impacts on health; however, the exact molecular mechanisms by which these deleterious effects occur are unknown. We hypothesize that fetal hypothyroidism during late gestation will disrupt cell cycle regulation in a tissue-specific manner. To evaluate this, eight pregnant gilts were dosed with either methimazole or an equivalent negative control during days 85-106 out of 114 days of gestation (n = 4/group). Following treatment, the gilts were humanely euthanized, and tissue samples of fetal heart, ileum, kidney, lung, liver, muscle, spleen, and thymus taken from two male and two female fetuses (n = 32) from each gilt. RESULTS: The relative expression of three cell cycle promoters (CDK1, CDK2, and CDK4), and one cell cycle inhibitor (CDKN1A) was compared in each tissue to determine the effect of hypothyroidism on the developing fetus. All of the eight tissues examined experienced at least one significant up- or downregulation in the expression of the aforementioned genes as a result of treatment with methimazole. Substantial changes were observed in the liver and muscle, with the latter experiencing significant downregulations of CDK1, CDK2, and CDK4 as a result of treatment. In addition, all tissues were examined for changes in protein content, which further elucidated the impact of hypothyroidism on the fetal liver by the observation of a marked increase in protein content in the methimazole-treated group. Finally, the heart and liver were histologically examined for evidence of cellular hyperplasia and hypertrophy by measuring average nuclei density and size in each tissue, with the results showing a significant decrease in average nuclei size in the liver of hypothyroid fetuses. CONCLUSIONS: Collectively, these findings indicate the occurrence of organ-specific disruptions in cell cycle progression as a result of in utero hypothyroidism, which may explain the long term and widespread effects of hypothyroidism on fetal development.

Recent Advances in the Discovery of Therapeutics to Curtail Islet Amyloid Polypeptide Aggregation for Type 2 Diabetes Treatment.

In humans with type 2 diabetes, at least 70% of patients exhibit islet amyloid plaques formed by misfolding islet amyloid polypeptides (IAPP). The oligomeric conformation and accumulation of the IAPP plaques lead to a panoply of cytotoxic effects on the islet ß-cells. Currently, no marketed therapies for the prevention or elimination of these amyloid deposits exist, and therefore significant efforts are required to address this gap. To date, most of the experimental treatments are limited to only in vitro stages of testing. In general, the proposed therapeutics use various targeting strategies, such as binding to the N-terminal region of islet amyloid polypeptide on residues 1-19 or the hydrophobic region of IAPP. Other strategies include targeting the peptide self-assembly through π-stacking. These methods are realized by using several different families of compounds, four of which are highlighted in this review: naturally occurring products, small molecules, organometallic compounds, and nanoparticles. Each of these categories holds immense potential to optimize and develop inhibitor(s) of pancreatic amyloidosis in the near future.