Mechanisms for Insulin Resistance in Polycystic Ovary Syndrome with metformin therapy: aminoadipic acid, lysine concentrations, and enrichment (part I)
Project description:Zika virus (ZIKV) can be transmitted vertically to the fetus, having a high chance to develop Congenital Zika Syndrome (CZS). Studies have shown that ZIKV impairs brain development. However, little is known about the molecular differences between non- microcephalic ZIKV-infected fetuses and microcephalic ones. Here, our main goal is to identify the alterations in the amniotic fluid (AF) metabolome in ZIKV-infected patients and their relation to CZS progression. We applied an untargeted metabolomics strategy to analyze seven AF of pregnant women: healthy women and ZIKV-infected women bearing non-microcephalic and microcephalic fetuses. Infected patients were characterized by glycerophospholipid metabolism impairment, which is accentuated in microcephalic phenotypes. Glycerophospholipid decreased concentration in AF can be a consequence of intracellular transport of lipids to the placental or fetal tissues under development. The increased intracellular concentration of lipids can lead to mitochondrial dysfunction and neurodegeneration caused by lipid droplet accumulation. Furthermore, the dysregulation of amino acid metabolism was a molecular fingerprint of microcephalic phenotypes, specifically serine, and proline metabolisms. Both amino acid deficiencies were related to neurodegenerative disorders, intrauterine growth retardation, and placental abnormalities. This study contributes to the understanding of CZS pathology and discovering potential biomarkers for CZS prognosis in the early stages of pregnancy.
Project description:The pathophysiological function of the FOXK family-member FOXK1 remains to be explored. Although tumors classically induce abnormalities in the insulin pathway, clinical trials have failed to establish insulin receptors as potential targets for tumor therapy. Metformin, so far has been identified as an effective treatment in several clinical oncology trials; however, metformin may fail to benefit all patients, and some even suffer from many side effects and drug resistance. Herein, we report that FOXK1 expression correlates with the sensitivity to metformin treatment in a variety of tumors. FOXK1 translocates into the nucleus in response to insulin stimulation and recruits multiple class I HDAC-containing complexes that regulate the expression of genes, such as PER2 and OGT, known to be critically involved in circadian rhythm and insulin resistance. Furthermore, high insulin levels associated with cancer could disturb the subcellular localization and epigenetic regulatory functions of FOXK1. Glycosylation modifications stabilize FOXK1 in the nucleus. Elevated nuclear FOXK1 competes with CLOCK for binding with BMAL1, leading to the deregulation of circadian rhythm, which, in turn, enhanced tumor cell proliferation in vitro and promoted tumor development in vivo. Correspondingly, elevated expression of nuclear FOXK1 was observed during tumor progression and was associated with a poor prognosis. Interestingly, both in vitro and in vivo experiments confirmed that cells with high FOXK1 expression were highly responsive to metformin stimulation. Collectively, these findings revealed that nuclear FOXK1 promotes tumorigenesis by disrupting circadian rhythm under insulin resistance, and its expression may serve as a potential indicator for the adjuvant treatment of tumors using metformin.