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81.
Although estrogens are neuroprotective in a variety of neuroprotection models, the precise underlying mechanisms are currently not well understood. Here, we examined the role of protein kinase C (PKC) in mediating estrogen-induced neuroprotection in the HT-22 immortalized hippocampal cell line. The neuroprotection model utilized calcein fluorescence to quantitate cell viability following glutamate insults. 17beta-Estradiol (betaE2) protected HT-22 cells when treatment was initiated before or after the glutamate insult. The inhibition of PKC by bis-indolylmaleimide mimicked and enhanced betaE2-induced neuroprotection. In contrast, the inhibition of specific PKC isozymes (alpha and beta) by Go6976, inhibition of 1-phosphatidylinositol 3 kinase by wortmannin, or inhibition of protein kinase A by H-89, did not alter cell viability, suggesting a specific involvement of PKC in an isozyme-dependent manner. We further examined whether estrogen interacts with PKC in a PKC isozyme-specific manner. Protein levels and activity of PKC isozymes (alpha, delta, epsilon, and zeta) were assessed by western blot analysis and radiolabeled phosphorylation assays respectively. Among the isozymes tested, betaE2 altered only PKCepsilon; it reduced the activity and membrane translocation of PKCepsilon in a manner that correlated with its protection against glutamate toxicity. Furthermore, betaE2 reversed the increased activity of membrane PKCepsilon induced by glutamate. These data suggest that the neuroprotective effects of estrogens are mediated in part by inhibition of PKCepsilon activity and membrane translocation. 相似文献
82.
Excessive activation of the hormone signaling pathways is implicated in several disorders of the target tissues, with cancer being one of the most serious fallouts. Steroid hormone receptors are key proteins through which steroid hormones convey their signals to the cells. Deregulated activity of the hormone receptors due to their altered activation; stability or sub-cellular localization is heavily implicated in the onset and progress of cancers. The role played by estrogen and its receptors in breast cancer remains the most thoroughly investigated steroid-dependent cancer system till date. Choosing it as an example, we have summarized the molecular mechanisms underlying the action of the estrogen receptors (ERs) in manifesting the effects of the estrogens in the cells. A special emphasis is placed on the molecular mechanism of their functionality, role of the coactivator proteins, and the reasons for the deregulated signaling. The therapeutic approaches resulting from the mechanistic study of the ER action and their efficacies are also discussed. 相似文献
83.
A.?V.?KamernitzkyEmail author I.?S.?Levina 《Russian Journal of Bioorganic Chemistry》2005,31(2):105-118
The synthesis, modification, structure, and biological activity in vivo of the 16,17- cycloalkanoprogesterone (pregna-D-pentarane) analogues of progesterone are described. A possibility of separation of their biological functions has been demonstrated. A systematic synthesis of a set of uniform compounds that differ in a limited number of alterable parameters was developed. It resulted in an instrument useful for the investigation of pathways and mechanisms by which the steroid hormones fulfill their biological functions and for the probable discovery of new functions masked by the wide effects of native compounds.__________Translated from Bioorganicheskaya Khimiya, Vol. 31, No. 2, 2005, pp. 115–129.Original Russian Text Copyright © 2005 by Kamernitzky, Levina.THE CYCLE OF WORKS OF THE AUTHORS DESCRIBED IN THE REVIEW HAS WON THE SHEMYAKIN PRIZE IN 2004 相似文献
84.
85.
Campbell BC Leslie PW Little MA Campbell KL 《American journal of physical anthropology》2005,128(4):896-905
The Turkana, like other East African pastoral groups, are known for their tall adult stature, achieved despite a blunted growth spurt during adolescence and continued growth into the early 20s. To investigate the hormonal mechanisms associated with the pattern of slow and continued adolescent growth, we collected data on hormonal status, height, weight, and trunk skinfolds and ethnographic self-reports of testicular maturation in a cross-sectional sample of 35 nomadic and 37 settled Turkana males aged 14-24. Hormonal determinations included testosterone (T), sex hormone-binding globulin (SHBG), and dehydroepiandrosterone (DHEA) in blood, in addition to urinary DHEA. Self-reports of testicular maturation showed no difference between settled and nomadic subpopulations. However, nomadic boys exhibited significantly higher levels of T, DHEA, and SHBG. Of all the hormones, only SHBG showed a significant relationship with age. Multiple regression models show blood T and SHBG to be significant independent predictors of achieved height as well as weight, controlling for age. Our results suggest that onset of puberty is substantially delayed among Turkana males, and that bioavailable T is related to growth in stature during adolescence. We suggest that SHBG acts to mediate the effects of energy availability on adolescent growth in this energetically limited population. Our findings may also have implications for understanding adolescent growth among Homo erectus. 相似文献
86.
The progesterone receptor (PR) is required for several aspects of mammalian female reproduction. PR null mice have overlapping defects that preclude an understanding of its multiple functions in ovulation, pregnancy, mammary gland biology, and sexual behavior. We have generated a PR conditional excision (PRCE) allele in which loxP sites flank exon 1. Homozygous PRCE females are fertile and appear to be functionally normal. Global cre mediated excision of the floxed exon 1 using EIIa-cre mice resulted in systemic loss of exon 1 and PR protein. Female mice homozygous for this null allele were sterile, as expected for PR knockout (PRKO) females. Conditional loss of PR will facilitate investigation of the spatial and temporal roles of PR in both normal development and disease. 相似文献
87.
All-trans retinoic acid and 9-cis-retinoic acid stimulate the activity of steroid sulfatase in HL60 acute myeloid leukemia cells in a concentration- and time-dependent manner. Neither of these 'natural retinoids' augmented steroid sulfatase activity in a HL60 sub-line that expresses a dominant-negative retinoic acid receptor alpha (RARalpha). Experiments with synthetic RAR and RXR agonists and antagonists suggest that RARalpha/RXR heterodimers play a role in the retinoid-stimulated increase in steroid sulfatase activity. The retinoid-driven increase in steroid sulfatase activity was attenuated by inhibition of phospholipase D (PLD), but not by inhibitors of phospholipase C. Experiments with inhibitors of protein kinase C (PKC) show that PKCalpha and PKCdelta play an important role in modulating the retinoid-stimulation of steroid sulfatase activity in HL60 cells. Furthermore, we show that pharmacological inhibition of the RAF-1 and ERK MAP kinases blocked the retinoid-stimulated increase in steroid sulfatase activity in HL60 cells and, by contrast, inhibition of the p38-MAP kinase or JNK-MAP kinase had no effect. Pharmacological inhibitors of the phosphatidylinositol 3-kinase, Akt, and PDK-1 also abrogated the retinoid-stimulated increase in steroid sulfatase activity in HL60 cells. These results show that crosstalk between the retinoid-stimulated genomic and non-genomic pathways is necessary to increase steroid sulfatase activity in HL60 cells. 相似文献
88.
Chiral O-(alpha-protected-aminoacyl)steroids 4a-f, 6a-b, 8 and 4a+4d and O-(alpha-protected-dipeptidoyl)steroids 12a,b are conveniently prepared under microwave irradiation in isolated yields of 65-96%, with complete chirality retention. The reaction utilized readily available N-(Z-alpha-aminoacyl)benzotriazoles 2a-f and Z-dipeptidoylbenzotriazole 11, with naturally occurring steroidal alcohols 3,5,7,9. 相似文献
89.
L. E. Golubovskaya Z. S. Smirnova V. N. Tolkachev V. M. Rzheznikov 《Russian Journal of Bioorganic Chemistry》2006,32(2):201-203
Esterification of 3-hydroxyl group in 11α-acyloxyestra-1,3,5(10)-trienes with p-[bis(2-chloroethyl)amino]phenyl acetic acid led to antitumor steroids displaying antiestrogenic and cytotoxic activities. Our substances exhibit their activities on the model of murine mammary adenocarcinoma Ca-755, with inhibition of the tumor growth being 94–99%. A new approach was used to the 11α-hydroxylation of estra-1,3,5(10)-trienes. 相似文献
90.
I Ben Charfeddine FG Riepe E Clauser A Ayedi S Makni MT Sfar H Sboui N Kahloul H Ben Hamouda S Chouchane S Trimech N Zouari S M'rabet F Amri A Saad PM Holterhus M Gribaa 《Gene》2012,507(1):20-26
Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease of steroid biosynthesis in humans. More than 90% of all CAH cases are caused by mutations of the 21-hydroxylase gene (CYP21A2), and approximately 75% of the defective CYP21A2 genes are generated through an intergenic recombination with the neighboring CYP21A1P pseudogene. In this study, the CYP21A2 gene was genotyped in 50 patients in Tunisia with the clinical diagnosis of 21-hydroxylase deficiency. CYP21A2 mutations were identified in 87% of the alleles. The most common point mutation in our population was the pseudogene specific variant p.Q318X (26%). Three novel single nucleotide polymorphism (SNP) loci were identified in the CYP21A2 gene which seems to be specific for the Tunisian population. The overall concordance between genotype and phenotype was 98%. With this study the molecular basis of CAH has been characterized, providing useful results for clinicians in terms of prediction of disease severity, genetic and prenatal counseling. 相似文献