Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is known that noradrenergic sympathetic nerve fibers connect the ovary and the spleen from the celiac ganglion. The modulation of the ovarian steroidogenesis in rats with polycystic ovary (PCO) by secretions of culture splenocytes from control (non PCO), PCO and PCO rats with superior ovarian nerve transection (PCO+SON-t) is investigated. Splenocytes from PCO rats increased progesterone (P) and decreasing estradiol (E) and androstenedione (A) release, a steroidogenic response different from that obtained with splenocytes of control rats. PCO also decreased the number of splenocyte beta-adrenergic receptors (betaR). SON transection reverted the effect of PCO on splenocytes betaR numbers and secretions of these splenocytes also reverted the stimulatory effect of PCO on P release, while norepinephrine (NE) treatment to PCO+SON-t splenocytes decreased their betaR number and their secretions restored the stimulation on progesterone release. Inversely, PCO+SON-t splenocyte secretions intensified the inhibition in estradiol with no effect on A. Treatment of PCO+SON-t splenocytes with NE or neuropeptide Y partially reverted the effects of PCO and SON-t The P and E-A response of PCO ovary might be differentially regulated by the splenocyte secretions through the neural connection involving ovary, SON, celiac ganglion and spleen and the neurotransmitter NE.
Cell Mol Biol (Noisy-le-grand) 2003 Sep
PMID:A neuroimmune regulation at peripheral level on the steroidogenesis of polycystic ovary in rats. 1465 55

Arrested follicular maturation is a characteristic feature of polycystic ovary syndrome (PCOS). Follicles mature in ovarian stroma composed of extracellular matrix (ECM). However, little is known of the expression of ECM genes in polycystic ovaries. The present study compares the expression levels of genes coding for collagens, matrix metalloproteinases (MMP), their inhibitors (TIMP) and cathepsins in polycystic ovaries using fertile and post-menopausal ovaries as controls. In northern analyses, the gene expression profiles of type I and III collagen of PCOS samples resembled those observed in normal follicular phase ovaries, while mRNA levels of proalpha1(IV) collagen and TIMP-3 mRNA were significantly lower in polycystic than control ovaries. During the normal menstrual cycle, an increase was observed in MMP-9 gene expression during the luteal phase. In post-menopausal ovaries, mRNA levels for type I, III and IV collagens and osteonectin were reduced, while the MMP, TIMP (excluding TIMP-3) and cathepsins did not reflect this metabolic down-regulation. Immunohistochemical staining for MMP-9 and TIMP-4 suggested differences between polycystic and normally functioning ovaries. These data demonstrate that normal ovarian functions are associated with changes in production and degradation of ECM. The alterations observed in the production and/or distribution of type IV collagen, TIMP-3 and TIMP-4 suggest involvement of basement membranes in the pathogenesis of PCOS.
Mol Hum Reprod 2004 Jan
PMID:Differences in connective tissue gene expression between normally functioning, polycystic and post-menopausal ovaries. 1466 1

Cytochrome P450 17alpha-hydroxylase (CYP17) gene expression and androgen biosynthesis are persistently elevated in theca cells isolated from ovaries of women with polycystic ovary syndrome (PCOS). We previously reported that -235 to -109 bp of the CYP17 promoter confers increased CYP17 promoter function in PCOS theca cells. In this report, additional deletion and mutational analyses of the CYP17 promoter were performed to identify the sequences that contribute to increased CYP17 promoter function in PCOS theca cells. Results of these analyses established that augmented promoter function in PCOS theca cells results from preferentially increased basal regulation conferred by sequences between -188 and -147 bp of the CYP17 promoter. Scanning mutant analysis demonstrated that mutations within a 16-bp sequence, spanning -174 to -158 bp of the promoter, ablated increased basal CYP17 promoter function in PCOS theca cells. EMSA analysis demonstrated that the NF-1 family member, NF-1C, bound this sequence. Cotransfection of several NF-1C isoforms expressed in normal and PCOS cells repressed CYP17 promoter function. NF-1C protein and DNA binding were reduced in PCOS theca cell nuclear extracts, as compared with normal. Another NF-1C site between -102 and -90 bp of the promoter was also identified. However, mutation of this site had no effect on differential promoter function in PCOS theca cells. These studies demonstrate that 1) augmented CYP17 promoter function in PCOS theca cells results from increased basal regulation, and 2) diminished NF-1C-dependent repression may be one mechanism underlying increased basal CYP17 promoter activity and altered gene expression in PCOS theca cells.
Mol Endocrinol 2004 Mar
PMID:Increased cytochrome P450 17alpha-hydroxylase promoter function in theca cells isolated from patients with polycystic ovary syndrome involves nuclear factor-1. 1468 46

The IGF2-INS-TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD). Here we present detailed haplotype analysis of 2743 males 51-62 years old in relation to body weight and composition, blood pressure (BP) and plasma triglycerides (TG). Use of the total data set was complicated by the number of loci typed, missing data, multi-allelic markers and continuous trait phenotypes. Different algorithms and subsets of the data were analysed using the programmes haplotype trend regression, haplo.score, evolutionary-based haplotype analysis package and Phase, in conjunction with SPSS. Ten haplotypes designated in frequency order *1(20.0%) to *10(3.4%) represented 89% of all haplotypes. Haplotype *5 protected against obesity. Haplotype *4 carriers exhibited elevated BP and fat mass, haplotype *6 was associated with raised plasma TG levels. Haplotype *8 also showed similar magnitude effects as *4. These cohort trait analyses and detailed haplotypic analyses enable integration with published case data. Haplotypes *4, *6 and *8 are the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displays unique features in all three genes (with significant commonality with type 1 diabetes-predisposition haplotypes). We propose that long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, predisposes to the metabolic syndrome features of elevated BP, fat mass or TG level, therefore appearing more frequently in type 2 diabetic, polycystic ovary syndrome and CHD cases. The functional element(s) of *5 for weight-lowering could reside in any of the three genes.
Hum Mol Genet 2004 Apr 01
PMID:Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits. 1474 49

Polycystic ovary disease (PCOD) is associated with insulin resistance and increased prevalence of type II diabetes mellitus (T2DM). The p21Ras/MAP kinase is a major intracellular signaling pathway mediating insulin signaling in insulin responsive tissues. The expression, regulation and function of the p21Ras/MAP kinase pathway in PCOD patients were examined. Peripheral blood mononuclear cells (PBMC) were isolated from ten patients with PCOD and ten controls. The expression of p21Ras and its regulatory proteins; hSOS1 and p120GAP were studied. The basal and phytohemaglutinin (PHA) or insulin stimulated phosphorylation of MAP kinase was determined. Expression of p21Ras, and its regulatory proteins hSOS1 and p120GAP were similar in PCOD patients and controls. Basal, PHA and insulin stimulated phosphorylation of MAP kinase, were also comparable in the two groups as well as their PBMC proliferative response. These data indicate that the expression and overall function of the p21Ras/MAP kinase pathway remain intact in non-diabetic patients with PCOD.
Int J Mol Med 2004 Apr
PMID:Normal p21Ras/MAP kinase pathway expression and function in PBMC from patients with polycystic ovary disease. 1501 Aug 62

Thiazolidinediones improve insulin sensitivity in type 2 diabetes mellitus by acting as peroxisome proliferator-associated receptor gamma (PPARgamma) agonists, and decrease circulating androgen concentrations in polycystic ovary syndrome by unknown mechanisms. Some thiazolidinediones directly inhibit the steroidogenic enzymes P450c17 and 3beta-hydroxysteroid dehydrogenase type II (3betaHSDII) by distinct mechanisms. We synthesized five novel thiazolidinediones, CLX-M1 to -M5 by linking a 2,4-thiazolidinedione moiety to a substituted alpha-phenyl cinnamic acid previously shown to have glucose-lowering effects. Using yeast microsomes expressing human P450c17 and 3betaHSDII we found that cinnamic acid methyl esters with a double bond in the thiazolidinedione core structure (M3, M5) were stronger inhibitors of P450c17 than methyl esters with the conventional core (M1, M4). These four compounds inhibited 3betaHSDII equally well, while the free cinnamic acid analog (M2) did not inhibit either enzyme. Thus, the inhibition of P450c17 and 3betaHSDII by these novel thiazolidinediones reveals structure-activity relationships independent of PPARgamma transactivation. PPARgamma transactivation was moderate (M1), weak (M2, M3) or even absent (M4, M5). While the PPARgamma agonist activity of M1 was only 3% of that of rosiglitazone, both increased glucose uptake by 3T3-L1 adipocytes and reduced serum glucose levels in ob/ob and db/db mice to a similar extent. The similar glucose-lowering effects of M1 and rosiglitazone, despite their vast differences in PPARgamma agonist activity, suggests these two actions may occur by separate mechanisms.
J Mol Endocrinol 2004 Apr
PMID:Cinnamic acid based thiazolidinediones inhibit human P450c17 and 3beta-hydroxysteroid dehydrogenase and improve insulin sensitivity independent of PPARgamma agonist activity. 1507 49

The elevated insulin concentrations that occur in many women with polycystic ovary syndrome (PCOS) can contribute significantly to ovarian hyperandrogenism. The objective of the present study was to compare the content of proximal insulin signalling molecules in theca and granulosa cells between polycystic ovaries and regular cycling controls. Individual follicles (3-7 mm) were obtained from 11 women with PCOS and 10 regularly cycling control women. The theca and granulosa cells were microdissected from each follicle. Total protein was extracted and signalling proteins were measured by western blot analysis. There was no difference in insulin receptor content between PCOS and controls in either theca or granulosa cells. Insulin receptor substrate (IRS)-1 and -2 were increased (P<0.05), but IRS-4 was decreased (P<0.03) in PCOS theca cells. There were no changes in IRS-1, -2 or -4 in granulosa cells. IRS-3 was undetectable in all samples. There were no changes in phosphatidyl inositol-3 kinase catalytic subunits p110alpha or p110beta in either theca or granulosa cells. These data demonstrate cell-specific alterations in IRS protein concentrations in theca cells from polycystic ovaries that are consistent with an exaggerated amplification of the insulin signal and which may play an important role in ovarian hyperandrogenism and thecal hyperplasia.
Mol Hum Reprod 2004 Jul
PMID:Selective alterations in insulin receptor substrates-1, -2 and -4 in theca but not granulosa cells from polycystic ovaries. 1515 16

Polycystic ovarian syndrome is seen in 5% of fertile aged women. However, there is no satisfactory PCOS model in experimental animals. To induce polycystic ovary phenotype in immature female rats, Wistar rats 21 days of age were injected daily with testosterone propionate 1 mg/100 g body weight dissolved in propylene glycol or propylene glycol for up to 35 days. Seven days of injection with testosterone (T) resulted in the appearance of large cystic follicles and a dramatic accumulation of multi-layer preantral follicles. At 42 days of age puberty in control animals was evident by the appearance of corpora lutea. In contrast in T treated animals no corpora lutea formation was seen even at the age of 56 days. Progesterone in the control animals was elevated at the age of 42 days in contrast with the T treated animals in which progesterone remained low (20% of control). While during 14 days of T injection most of the follicles did not have progressive apoptosis, at 21-35 days of injection (42-56 days of age) the vast majority of follicles became apoptotic. Progressive degeneration of oocytes was evident in T treated animals reaching 70-85% of total oocytes at 21-35 days of T injection compared to 30-40% in control animals. Western blot analysis of ovarian homogenates revealed gradual decrease in Bcl-2 content, evident at 28 and 35 days of T injection compared to control animals. Interestingly, the fasting glucose/insulin ratio was dramatically reduced in T treated animals following 14 days of testosterone treatment compared to controls. Our data suggest that T injection to immature female rats can induce polycystic ovaries, block ovulation and attenuate progesterone production. Moreover, normal/low glucose and high insulin blood levels in the testosterone treated rats raises the possibility that elevated androgens can lead to insulin resistance in this experimental PCOS model.
Int J Mol Med 2004 Aug
PMID:Induction of polycystic ovary by testosterone in immature female rats: Modulation of apoptosis and attenuation of glucose/insulin ratio. 1525 67

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders; it is characterized by polycystic ovaries, hyperandrogenism and chronic anovulation. To obtain a global view of those genes that might be involved in the development of this complex clinical disorder, we used recently developed cDNA microarray technology to compare differential gene expressions between normal human ovary and ovaries from PCOS patients. A total of 9216 clones randomly selected from a commercial human ovary cDNA library were screened. Among them, 290 clones showed differential expressions, including 119 known genes and 100 known or unknown expressed sequence tags (ESTs). Among 119 known genes, 88 were upregulated and 31 downregulated in the PCOS ovary, as compared with normal human ovary. These differentially expressed genes are involved in various biologic functions, such as cell division/apoptosis, regulation of gene expression and metabolism, reflecting the complexity of clinical manifestations of PCOS. The molecular characteristics established from our study will further our understanding of the pathogenesis of PCOS and help us to identify new targets for further studies and for the development of new therapeutic interventions.
J Mol Endocrinol 2004 Aug
PMID:The molecular characteristics of polycystic ovary syndrome (PCOS) ovary defined by human ovary cDNA microarray. 1529 43

Polycystic ovary syndrome (PCOS) represents the most common cause of anovulatory infertility and affects 5-10% of women of reproductive age. The etiology of PCOS is still unknown. The current study is the first to describe consistent differences in gene expression profiles in human ovaries comparing PCOS patients vs. healthy normoovulatory individuals. The microarray analysis of PCOS vs. normal ovaries identifies dysregulated expression of genes encoding components of several biological pathways or systems such as Wnt signaling, extracellular matrix components, and immunological factors. Resulting data may provide novel clues for ovarian dysfunction in PCOS. Intriguingly, the gene expression profiles of ovaries from (long-term) androgen-treated female-to-male transsexuals (TSX) show considerable overlap with PCOS. This observation provides supportive evidence that androgens play a key role in the pathogenesis of PCOS. Presented data may contribute to a better understanding of dysregulated pathways in PCOS, which might ultimately reveal novel leads for therapeutic intervention.
Mol Endocrinol 2004 Dec
PMID:Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients. 1530 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>