Effect of Cynomorium total flavone on depression model of perimenopausal rat

PurposeTo observe the effect of cynomorium total flavone on the depression model of perimenopausal rat and to analyze the action characteristics of cynomorium total flavone on depression of rat with perimenopausal syndrome.MethodDuplicate the model of rat with perimenopausal depression based on the combined method of incomplete castration and chronic stimulation, and keep drug administration for 35d. And then measure related behavior indicators and the change of biochemical index level in serum and brains; measure the estrogen/androgen receptor (ER/AR) in related tissues and the ERmRNA expression in hypothalamus.ResultIt can be seen that cynomorium total flavone can significantly improve the behavior indicators of rat with perimenopausal depression; obviously or significantly change the level of related biomedical indexes in serum and brains of perimenopausal depressed rat; obviously or significantly increase the expression of ER/AR in related tissues of perimenopausal depressed rat; obviously or significantly increase the ERmRNA expression in hypothalamus.ConclusionCynomorium total flavone can adjust hypothalamic-pituitary-gonadal axis by increasing E2, and make related biomedical indexes and hormone receptors tend to be normal, so as to relieve perimenopausal syndrome and perimenopausal syndrome with depression.     

Small molecule mimetics of an interferon-α receptor interacting domain

Small molecules that mimic IFN-α epitopes that interact with the cell surface receptor, IFNAR, would be useful therapeutics. One such 8-amino acid region in IFN-α2, designated IRRP-1, was used to derive 11 chemical compounds that belong to 5 distinct chemotypes, containing the molecular features represented by the key residues Leu30, Arg33, and Asp35 in IRRP-1. Three of these compounds exhibited potential mimicry to IRRP-1 and, in cell based assays, as predicted, effectively inhibited IFNAR activation by IFN-α. Of these, compound 3 did not display cell toxicity and reduced IFN-α-inducible STAT1 phosphorylation and STAT-DNA binding. Based on physicochemical properties’ analyses, our data suggest that moieties with acidic pKa on the small molecule may be a necessary element for mimicking the carboxyl group of Asp35 in IRRP-1. Our data confirm the relevance of this strategy of molecular mimicry of ligand–receptor interaction domains of protein partners for small molecule drug discovery.     

Sodium Fluoride Mimics the Effect of Prostaglandin E2 on Catecholamine Release from Bovine Adrenal Chromaffin Cells

We have reported recently that prostaglandin E2 (PGE2) stimulated phosphoinositide metabolism in bovine adrenal chromaffin cells and that PGE2 and ouabain, an inhibitor of Na+, K(+)-ATPase, synergistically induced a gradual secretion of catecholamines from the cells. Here we examined the involvement of a GTP-binding protein(s) in PGE receptor-induced responses by using NaF. In the presence of Ca2+ in the medium, NaF stimulated the formation of all three inositol phosphates, i.e., inositol monophosphate, bisphosphate, and trisphosphate, linearly over 30 min in a dose-dependent manner (15-30 mM). This effect on phosphoinositide metabolism was accompanied by an increase in cytosolic free Ca2+. NaF also induced catecholamine release from chromaffin cells, and the dependency of stimulation of the release on NaF concentration was well correlated with those of NaF-enhanced inositol phosphate formation and increase in cytosolic free Ca2+. Although the effect of NaF on PGE2-induced catecholamine release in the presence of ouabain was additive at concentrations below 20 mM, there was no additive effect at 25 mM NaF. Furthermore, the time course of catecholamine release stimulated by 20 mM NaF in the presence of ouabain was quite similar to that by 1 microM PGE2, and both stimulations were markedly inhibited by amiloride, with half-maximal inhibition at 10 microM. Pretreatment of the cells with pertussis toxin did not prevent, but rather enhanced, PGE2-induced catecholamine release over the range of concentrations examined. These results demonstrate that NaF mimics the effect of PGE2 on catecholamine release from chromaffin cells and suggest that PGE2-evoked catecholamine release may be mediated by the stimulation of phosphoinositide metabolism through a putative GTP-binding protein insensitive to pertussis toxin.     

Galanin Signaling in the Brain Regulates Color Pattern Formation in Zebrafish

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Remarkable genetic diversity detected at river buffalo prolactin receptor (PRLR) gene and association studies with milk fatty acid composition

Prolactin is an anterior pituitary peptide hormone involved in many different endocrine activities and is essential for reproductive performance. This action is mediated by its receptor, the prolactin receptor, encoded by the PRLR gene. In this study, we sequenced and characterized the Mediterranean river buffalo PRLR gene (from exon 3 to 10), and we found remarkable genetic diversity. In particular, we found 24 intronic polymorphisms and 13 exonic SNPs, seven of which were non‐synonymous. Furthermore, the polymorphisms identified in the 3′‐UTR were investigated to establish their possible influence on microRNA binding sites. Considering all the amino acid changes and the observed allelic combinations, it is possible to deduce at least six different translations of the buffalo prolactin receptor and, consequently, the presence at the PRLR gene of at least six alleles. Furthermore, we identified a deletion of a CACTACC heptamer between nucleotides 1102 and 1103 of exon 10 (3′‐UTR), and we developed an allele‐specific PCR to identify the carriers of this genetic marker. Finally, the SNP g.11188A>G, detected in exon 10 and responsible for the amino acid replacement p.His328Arg, was genotyped in 308 Italian Mediterranean river buffaloes, and an association study with milk fat traits was carried out. The statistical analysis showed a tendency that approached significance for the AA genotype with higher contents of odd branched‐chain fatty acids. Thus, our results suggest that the PRLR gene is a good candidate for gene association studies with qualitative traits related to buffalo milk production.     

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles

Generation of the soluble interleukin-6 receptor (sIL-6R) is a prerequisite for pathogenic IL-6 trans-signaling, which constitutes a distinct signaling pathway of the pleiotropic cytokine interleukin-6 (IL-6). Although in vitro experiments using ectopically overexpressed IL-6R and candidate proteases revealed major roles for the metalloproteinases ADAM10 and ADAM17 in IL-6R shedding, the identity of the protease(s) cleaving IL-6R in more physiological settings, or even in vivo, remains unknown. By taking advantage of specific pharmacological inhibitors and primary cells from ADAM-deficient mice we established that endogenous IL-6R of both human and murine origin is shed by ADAM17 in an induced manner, whereas constitutive release of endogenous IL-6R is largely mediated by ADAM10. Although circulating IL-6R levels are altered in various diseases, the origin of blood-borne IL-6R is still poorly understood. It has been shown previously that ADAM17 hypomorphic mice exhibit unaltered levels of serum sIL-6R. Here, by quantification of serum sIL-6R in protease-deficient mice as well as human patients we also excluded ADAM10, ADAM8, neutrophil elastase, cathepsin G, and proteinase 3 from contributing to circulating sIL-6R. Furthermore, we ruled out alternative splicing of the IL-6R mRNA as a potential source of circulating sIL-6R in the mouse. Instead, we found full-length IL-6R on circulating microvesicles, establishing microvesicle release as a novel mechanism for sIL-6R generation.     

Activation of OR1A1 suppresses PPAR-γ expression by inducing HES-1 in cultured hepatocytes

Olfactory receptors (ORs) comprise the largest G protein-coupled receptor gene superfamily. Recent studies indicate that ORs are also expressed in non-olfactory organs, including metabolically active tissues, although their biological functions in these tissues are largely unknown. In this study, OR1A1 expression was detected in HepG2 liver cells. OR1A1 activation by (−)-carvone, a known OR1A1 ligand, increased the cyclic adenosine monophosphate (cAMP), but not intracellular Ca²⁺ concentration, thereby inducing protein kinase A (PKA) activity with subsequent phosphorylation of cAMP response element-binding protein (CREB) and upregulation of the CREB-responsive gene hairy and enhancer of split (HES)-1, a corepressor of peroxisome proliferator-activated receptor-γ (PPAR-γ) in hepatocytes. In (−)-carvone-stimulated cells, the repression of PPAR-γ reduced the expression of the target gene, mitochondrial glycerol-3-phosphate acyltransferase, which encodes a key enzyme involved in triglyceride synthesis. Intracellular triglyceride level and lipid accumulation were reduced in cells stimulated with (−)-carvone, effects that were diminished following the loss of OR1A1 function. These results indicate that OR1A1 may function as a non-redundant receptor in hepatocytes that regulates the PKA-CREB-HES-1 signaling axis and thereby modulates hepatic triglyceride metabolism.