Volume 29, Issue 1

There are two forms of immune defense, the specific or adaptive immune defense and the unspecific innate immune defense. Vaccination is utilized against specific bacteria via the adaptive immune system. The innate immunity DNA stress defense is a non-toxic mechanism developed in yeasts and conserved in mammals and in plants. Although the steroidal hormone cascade has overtaken the stress response and allows superfast response via non-genomic receptors, the old innate immunity response is still mediated via the steroidal hormones cascade. The classical drug/receptor model has provided for many solutions, however, in antibiotics, cancer, and in severe mental diseases this model reaches to certain limits. The NIH/Department of Mental Health has developed a new model that shows severe mental diseases may be immune diseases that can be treated by replacing old diseased nerve cells by new healthy nerve cells, where the old innate immunity may be exploited. This means that severe mental diseases are physical diseases. A newly developed model, where modifications of the steroidal hormone cascade help to understand bipolarity, schizophrenia, and PTSD in men and women can be transferred to gynecological hormone modifications in women, where innate immunity is mediated via the same steroidal hormone cascade. Treatment via immune response via the DNA cascade should be developed in cancer, infections and severe mental disease, because foreign cells or diseased cells may be removed by the unspecific innate immunity.

Both functional ovaries and estrogen replacement therapy (ERT) reduce the risk of type 2 diabetes (T2D). Understanding the mechanisms underlying the antidiabetic effects of 17β-estradiol (E2) may permit the development of a molecular targeting strategy for the treatment of metabolic disease. This study examines how the promotion of insulin sensitivity and weight loss by E2 treatment in high-fat-diet (HFD)-fed mice involve several anti-adipogenic processes in the visceral adipose tissue. Magnetic resonance imaging (MRI) revealed specific reductions in visceral adipose tissue volume in HFD+E2 mice, compared with HFD mice. This loss of adiposity was associated with diminished visceral adipocyte size and reductions in expression of lipogenic genes, adipokines and of the nuclear receptor nr2c2/tr4 . Meanwhile, expression levels of adipose triglyceride lipase/ pnpla2 and leptin receptor were increased. As mRNA levels of stat3 , a transcription factor involved in brown adipose tissue differentiation, were also increased in visceral adipose, the expression of other brown adipose-specific markers was assessed. Both expression and immunohistochemical staining of ucp-1 were increased, and mRNA levels of dio-2 , and of adrβ3 , a regulator of ucp-1 expression during the thermogenic response, were increased. Furthermore, expression of cpt-1b , a brown adipose-specific gene involved in fatty acid utilization, was also increased. Methylation studies demonstrated that the methylation status of both dio-2 and adrβ3 was significantly reduced. These results show that improved glycemic control and weight loss due to E2 involve anti-adipogenic mechanisms which include suppressed lipogenesis and augmented fatty acid utilization, and in addition, the activation of brown adipose tissue-specific gene expression in association with E2-dependent epigenetic modifications in these genes.

Human cytosolic sulfotransferase 1C4 (hSULT1C4) is a dimeric Phase II drug-metabolizing enzyme primarily expressed in the developing fetus. SULTs facilitate the transfer of a hydrophilic sulfonate moiety from 3′-phosphoadenosine-5′-phosphosulfate (PAPS) onto an acceptor substrate altering the substrate’s biological activity and increasing the compound’s water solubility. While several of the hSULTs’ endogenous and xenobiotic substrates have been identified, the physiological function of hSULT1C4 remains unknown. The fetal expression of hSULT1C4 leads to the hypothesis that the function of this enzyme may be to regulate metabolic and hormonal signaling molecules, such as estrogenic compounds, that may be generated or consumed by the mother during fetal development. Human SULT1C4 has previously been shown to sulfonate estrogenic compounds, such as catechol estrogens; therefore, this study focused on the expression and purification of hSULT1C4 in order to further characterize this enzyme’s sulfonation of estrogenic compounds. Molecular modeling of the enzyme’s native properties helped to establish a novel purification protocol for hSULT1C4. The optimal activity assay conditions for hSULT1C4 were determined to be pH 7.4 at 37°C for up to 10 min. Kinetic analysis revealed the enzyme’s reduced affinity for PAPS compared to PAP. Human SULT1C4 sulfonated all the estrogenic compounds tested, including dietary flavonoids and environmental estrogens; however, the enzyme has a higher affinity for sulfonation of flavonoids. These results suggest hSULT1C4 could be metabolizing and regulating hormone signaling pathways during human fetal development.