Effects of Thyroid Hormone on Tissue Hypoxia: Relevance to Sepsis Therapy

Tissue hypoxia occurs in various conditions such as myocardial or brain ischemia and infarction, sepsis, and trauma, and induces cellular damage and tissue remodeling with recapitulation of fetal-like reprogramming, which eventually results in organ failure. Analogies seem to exist between the damaged hypoxic and developing organs, indicating that a regulatory network which drives embryonic organ development may control aspects of heart (or tissue) repair. In this context, thyroid hormone (TH), which is a critical regulator of organ maturation, physiologic angiogenesis, and mitochondrial biogenesis during fetal development, may be of important physiological relevance upon stress (hypoxia)-induced fetal reprogramming. TH signaling has been implicated in hypoxic tissue remodeling after myocardial infarction and T3 prevents remodeling of the postinfarcted heart. Similarly, preliminary experimental evidence suggests that T3 can prevent early tissue hypoxia during sepsis with important physiological consequences. Thus, based on common pathways between different paradigms, we propose a possible role of TH in tissue hypoxia after sepsis with the potential to reduce secondary organ failure.

Quantifying Fetal Reprogramming for Biomarker Development in the Era of High-Throughput Sequencing

Gestational hypertensive disorders continue to threaten the well-being of pregnant women and their offspring. The only current definitive treatment for gestational hypertensive disorders is delivery of the fetus. The optimal timing of delivery remains controversial. Currently, the available clinical tools do not allow for assessment of fetal stress in its early stages. Placental insufficiency and fetal growth restriction secondary to gestational hypertensive disorders have been shown to have long-term impacts on offspring health even into their adulthood, becoming one of the major focuses of research in the field of developmental origins of health and disease. Fetal reprogramming was introduced to describe the long-lasting effects of the toxic intrauterine environment on the growing fetus. With the advent of high-throughput sequencing, there have been major advances in research attempting to quantify fetal reprogramming. Moreover, genes that are found to be differentially expressed as a result of fetal reprogramming show promise in the development of transcriptional biomarkers for clinical use in detecting fetal response to placental insufficiency. In this review, we will review key pathophysiology in the development of placental insufficiency, existing literature on high-throughput sequencing in the study of fetal reprogramming, and considerations regarding research design from our own experience.

Integrated Analysis of Key Genes and Pathways Involved in Fetal Growth Restriction and Their Associations With the Dysregulation of the Maternal Immune System

Fetal growth restriction (FGR) is a common pregnancy complication and a risk factor for infant death. Most patients with FGR have preeclampsia, gestational diabetes mellitus, or other etiologies, making it difficult to determine the specific molecular mechanisms underlying FGR. In this study, an integrated analysis was performed using gene expression profiles obtained from Gene Expression Omnibus. Differentially expressed genes (DEGs) between healthy and FGR groups were screened and evaluated by functional enrichment and network analyses. In total, 80 common DEGs (FDR < 0.05) and 17 significant DEGs (FDR < 0.005) were screened. These genes were enriched for functions in immune system dysregulation in the placenta based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Among hub genes identified as candidates for FGR and fetal reprogramming, LEP, GBP5, HLA–DQA1, and CTGF were checked by quantitative polymerase chain reaction, immunohistochemistry, and western blot assays in placental tissues. Immune imbalance could cause hypoxia environment in placenta tissues, thus regulating the fetal-reprogramming. A significant association between CTGF and HIF-1α levels was confirmed in placenta tissues and HTR8 cells under hypoxia. Our results suggest that an immune imbalance in the placenta causes FGR without other complications. We provide the first evidence for roles of CTGF in FGR and show that CTGF may function via HIF-1α-related pathways. Our findings elucidate the pathogenesis of FGR and provide new therapeutic targets.

Heart failure and the glutathione cycle: an integrated view

Heart failure results from the heart's inability to carryout ventricular contraction and relaxation, and has now become a worldwide problem. During the onset of heart failure, several signatures are observed in cardiomyocytes that includes fetal reprogramming of gene expression where adult genes are repressed and fetal genes turned on, endoplasmic reticulum stress and oxidative stress. In this short review and analysis, we examine these different phenomenon from the viewpoint of the glutathione cycle and the role of the recently discovered Chac1 enzyme. Chac1, which belongs to the family of γ-glutamylcyclotransferases, is a recently discovered member of the glutathione cycle, being involved in the cytosolic degradation of glutathione. This enzyme is induced during the Endoplasmic Stress response, but also in the developing heart. Owing to its exclusive action on reduced glutathione, its induction leads to an increase in the oxidative redox potential of the cell that also serves as signaling mechanism for calcium ions channel activation. The end product of Chac1 action is 5-oxoproline, and studies with 5-oxoprolinase (OPLAH), an enzyme of the glutathione cycle has revealed that down-regulation of OPLAH can lead to the accumulation of 5-oxproline which is an important factor in heart failure. With these recent findings, we have re-examined the roles and regulation of the enzymes in the glutathione cycle which are central to these responses. We present an integrated view of the glutathione cycle in the cellular response to heart failure.

The MEK/ERK Module Is Reprogrammed in Remodeling Adult Cardiomyocytes

Fetal and hypertrophic remodeling are hallmarks of cardiac restructuring leading chronically to heart failure. Since the Ras/Raf/MEK/ERK cascade (MAPK) is involved in the development of heart failure, we hypothesized, first, that fetal remodeling is different from hypertrophy and, second, that remodeling of the MAPK occurs. To test our hypothesis, we analyzed models of cultured adult rat cardiomyocytes as well as investigated myocytes in the failing human myocardium by western blot and confocal microscopy. Fetal remodeling was induced through endothelial morphogens and monitored by the reexpression of Acta2, Actn1, and Actb. Serum-induced hypertrophy was determined by increased surface size and protein content of cardiomyocytes. Serum and morphogens caused reprogramming of Ras/Raf/MEK/ERK. In both models H-Ras, N-Ras, Rap2, B- and C-Raf, MEK1/2 as well as ERK1/2 increased while K-Ras was downregulated. Atrophy, MAPK-dependent ischemic resistance, loss of A-Raf, and reexpression of Rap1 and Erk3 highlighted fetal remodeling, while A-Raf accumulation marked hypertrophy. The knock-down of B-Raf by siRNA reduced MAPK activation and fetal reprogramming. In conclusion, we demonstrate that fetal and hypertrophic remodeling are independent processes and involve reprogramming of the MAPK.

NAFLD at the Interface of the Mother-Infant Dyad

: This review aims to focus the links existing between several aspects of the mother-child dyad in the intricate playground of obesity and Metabolic Syndrome (MetS), including its hepatic component, the Non- Alcoholic Fatty Liver Disease (NAFLD). In recent years human and animal model studies have shown that dietary interventions in mothers and offspring can be successful in reducing the risk of NAFLD development. Evidences also concern the new concept of a real intergenerational transmission of predisposition to metabolic disorders. Certain genes, such as SIRT1 and PNPLA3, and some epigenetic modifications, including micro RNAs function, seem to be responsible for fetal reprogramming in the setting of maternal obesity. These modifiers appear to be potential therapeutic targets to reduce the risk of future metabolic dysfunctions. : Controlling antepartum hyperglycemia, preventing gestational diabetes, and avoiding excessive weight gain during pregnancy can help reduce the relentless epidemic of childhood obesity and NAFLD. Also, the composition of the intestinal microbiota seems to be related to the development of metabolic disorders in the offspring. Several studies show that breastfed infants have a microbial signature different from formula-fed infants. Much interestingly, prolonged breastfeeding is beneficial not only for the newborn and his health in adult life, but also for the mothers’ health. Maternal benefits include reducing the risk of developing chronic diseases, such as diabetes mellitus, myocardial infarction and NAFLD as well. : In conclusion, all above mechanisms appear to intervene synergistically and may act as modifiable risk factors for infant and mother NAFLD.