Mammary gland development is controlled by a dynamic interplay between endocrine hormones and locally produced factors. Biogenic monoamines (serotonin, dopamine, norepinephrine, and others) are an important class of bioregulatory molecules that have not been shown to participate in mammary development. Here we show that mammary glands stimulated by prolactin (PRL) express genes essential for serotonin biosynthesis (tryptophan hydroxylase [TPH] and aromatic amine decarboxylase). TPH mRNA was elevated during pregnancy and lactation, and serotonin was detected in the mammary epithelium and in milk. TPH was induced by PRL in mammosphere cultures and by milk stasis in nursing dams, suggesting that the gene is controlled by milk filling in the alveoli. Serotonin suppressed beta-casein gene expression and caused shrinkage of mammary alveoli. Conversely, TPH1 gene disruption or antiserotonergic drugs resulted in enhanced secretory features and alveolar dilation. Thus, autocrine-paracrine serotonin signaling is an important regulator of mammary homeostasis and early involution.
Our work represents a detailed description of the morphometric and cellular phenotypic lesions present in the veins of CKD and ESRD patients, prior to dialysis access placement. These studies (i) suggest the future possibility of a new predictive marker (pre-existing venous neointimal hyperplasia) for AV dialysis access dysfunction and (ii) open the door for the future development of novel local therapies for optimization of the venous substrate on which the dialysis access is created.
Apoliprotein E (apoE) is a potent suppressor of interleukin 2- (IL2-) dependent T lymphocyte proliferation. In this study, we have used a range of monomeric and dimeric peptides encompassing amino acids 130-169 in human apoE to locate a region with both cytostatic and cytotoxic effects on IL2-dependent T lymphocytes. Monomeric peptides representing residues 130-149 or 130-155 inhibited the proliferation of the cells without causing loss of cell viability. However, cytostasis by a peptide representing the extended 130-169 domain or dimeric peptides of amino acids 141-155 or 141-149 was accompanied by potent cytotoxic activity. These results suggest that residues 141-149, which include the overlap between the functional peptides, are responsible for cytostasis and cytotoxicity. Complete ablation of both activities by the polyanionic agent heparin highlighted the important contribution of the positively charged amino acids in the 141-149 region to peptide bioactivity. Furthermore, the bioactive apoE peptides also had a relatively high helical content, suggesting that alpha-helical content is necessary for bioactivity. Cytotoxic apoE peptides were characterized by a high density of polar face positively charged residues together with a high nonpolar face hydrophobicity. This conclusion is supported by the reduced hydrophobicity and polar face positive charge density of the significantly less active E2(130-169) peptide. The cytotoxic apoE peptides are structurally similar to previously characterized class L lytic peptides. They do not, however, exert their cytotoxic activity by destabilizing membrane bilayers as is the case with the class L peptides, as evidenced by their minimal hemolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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