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)

The morphology of the mouse vas deferens still undergoes major changes from birth to 40 days of age, such as differentiation of the mesenchymal cells into fibroblasts and muscle cells, differentiation of the epithelium into basal and columnar epithelial cells, development of stereocilia, and the appearance of smooth endoplasmic reticulum organised in fingerprint-like structures or parallel, flattened saccules. In mutant homozygous DeltaF508 (DeltaF/DeltaF) and knock-out (cf/cf) CFTR mice, strain 129/FvB and 129/C57BL-6, respectively, a similar development occurred until the age of 20 days. At 40 days, however, the lumen was filled with eosinophilic secretions, and sperm cells were absent in the majority of the animals examined, although sperm production in testis and epididymis appeared to be normal. CFTR was localised in the apical membrane and cytoplasm of the vas deferens epithelium from 40 days on but could not be detected in the vas deferens before 20 days or in mutant adult CFTR mice as expected. Western blots of membrane preparations showed that the mature form of CFTR was present in vas deferens and testis but absent in seminal vesicles. Our results suggest that the function of CFTR is probably essential after 20 days in the vas deferens and that its absence or dysfunction may result in a vas deferens with a differentiated epithelium but a collapsed lumen, which could at least temporarily delay the transport of spermatozoa. These observations contrast with those made in the overall majority of CF patients. Mol. Reprod. Dev. 55:125-135, 2000.
Mol Reprod Dev 2000 Feb
PMID:Morphological changes in the vas deferens and expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in control, deltaF508 and knock-out CFTR mice during postnatal life. 1061 51

17-Azolyl steroids were synthesized and evaluated as inhibitors of androgen synthesis in vitro and in vivo. Several of the novel compounds exhibit potent noncompetitive inhibition of human 17alpha-hydroxylase/C17,20-lyase with IC50 values ranging from 7 to 90 nM, and Ki values from 1.2 to 41 nM. VN/85-1 and VN/108-1 were the most potent inhibitors against this enzyme with IC50 value of 8 nM (Ki of 1.2 nM) and 7 nM (Ki of 1.9 nM), respectively. VN/107-1, VN/108-1 and VN/109-1 also showed moderate inhibition of 5alpha-reductase in human prostatic microsomes. Normal adult male rats were treated with these novel 17-azolyl steroidal compounds at a dose level of 50 mg/kg, s.c., for 14 consecutive days, sacrificed 1-2 h after the last administered dose and blood, prostate and other tissues were collected. The organs were weighed and tissue concentrations of testosterone (T) and dihydrotestosterone (DHT) were measured. Tissue T levels were significantly (p<0.05) lower in rats treated with the novel 17-azolyl steroids by more than 50% compared to the control group. Similarly, the concentration of DHT in the serum and prostates was significantly (p<0.05) diminished in rats treated with the 17-azolyl steroids by 39-80% compared to the control group. Furthermore, the wet weights of the prostates and seminal vesicles were significantly (p<0.05) reduced by several of the novel steroids. Although only one dose was evaluated in these studies, VN/85-1 was the most effective compound and reduced prostatic androgen levels by more than 80% and the wet weights of the prostate and seminal vesicles in rats by about 50%. These findings suggest that these novel compounds may provide useful leads for the research and development of suitable agents for the treatment of androgen dependent prostate cancer.
J Steroid Biochem Mol Biol 1999 Dec 15
PMID:Effects of novel 17-azolyl compounds on androgen synthesis in vitro and in vivo. 1065 3

Adenovirus-mediated gene transfer may hold much promise in the treatment of human cancer. However, concerns regarding vector dissemination beyond the target tissue, particularly with replication-competent viruses, require an evaluation of the persistence of viral infection in collateral tissue and vector-associated toxicities. In addition, for indications such as prostate cancer, the proximity of the point of viral administration to organs of the male reproductive system raises concerns regarding inadvertent germ-line transmission of genes carried by the virus. To address these concerns, the biodistribution, persistence, toxicity, and potential of germ-line transmission of a replication-competent adenovirus (Ad5-CD/TKrep) following intraprostatic administration in the mouse was examined. Ad5-CD/TKrep (10(10) vp, 5 x 10(11) vp/kg) was injected intraprostatically on Day 1 of the study and its presence in the major organs of the male urogenital tract (prostate, testes, seminal vesicles, and urinary bladder) and liver was determined on Days 8 and 29. For comparison, a parallel group of animals was injected with the same dose of a related replication-defective Ad5-FGNR virus. To evaluate germ-line transmission, Ad5-CD/TKrep-injected males were mated to females on Days 8 and 29 and resulting embryos were examined for AdS-CD/TKrep viral DNA. Ad5-CD/TKrep viral DNA was detected in all major organs of the adult male urogenital tract and liver 7 and 28 Days postinjection. Interestingly, relative to the replication-defective Ad5-FGNR adenovirus, the replication-competent Ad5-CD/TKrep virus accumulated to a much greater level (approximately 300-fold) and persisted for a longer period of time in prostate, testes, and liver. This difference could not be explained on the basis of differences in viral infectivity, suggesting that the AdS-CD/TKrep virus may be capable of replicating in mouse tissues in vivo. In vitro infection of six mouse cell lines representing prostate, testes, and liver demonstrated that the Ad5-CD/TKrep virus was indeed capable of replicating in these mouse cell types, albeit with reduced efficiencies relative to human cells. Despite the fact that the Ad5-CD/TKrep vector persisted in the adult male gonads and may have replicated in vivo, we observed no evidence of germ-line transmission in 149 offspring examined. To evaluate the toxicity of combining Ad5-CD/TKrep viral therapy with CD/5-FC and HSV-1 TK/GCV suicide gene therapies as a prerequisite for a human trial, an escalating dose (10(8), 10(9), 10(10) vp) of Ad5-CD/TKrep was administered intraprostatically followed by 7 days of 5-FC and GCV double prodrug therapy. Although the virus persisted in the mouse urogenital tract and liver for up to 28 days postinjection, most of the toxicities observed were expected, minimal, and self-limiting. These results lead us to believe that intraprostatic administration of the Ad5-CD/TKrep virus to humans concomitant with double suicide gene therapy will be associated with acceptable toxicities and will not result in vertical transmission of viral-encoded genes through the germ line.
Mol Ther 2000 Mar
PMID:Evaluation of the biodistribution, persistence, toxicity, and potential of germ-line transmission of a replication-competent human adenovirus following intraprostatic administration in the mouse. 1093 42

It is known that lower-chlorinated biphenyls are metabolically activated to electrophilic quinoid species capable of binding to DNA. Also, certain metabolites are capable of redox cycling, thereby increasing oxidative stress in biological systems. In the present study, we tested mono-, di-, tri-, tetra-, penta-, hexa-, and heptachlorinated biphenyls for their ability to bind with DNA and to induce oxidative DNA damage. We present additional evidence that several PCB congeners form DNA adducts after metabolic activation, which can be detected by the nuclease P1- or butanol-enrichment procedures of the (32)P-postlabeling technique. Butanol and nuclease P1 enrichments showed different adduct recoveries, depending on the level of chlorination of the biphenyls. Application of the nuclease P1 enrichment showed that the incubation of 2-chloro-; 3, 4-dichloro-; 2,4,4'-trichloro-; 3,4,5-trichloro-; and 2,2',5, 5'-tetrachlorobiphenyl with calf thymus DNA and liver microsomes from rats treated with phenobarbital, followed by oxidation with a peroxidase, produced five to eight different DNA adducts. For these lower-chlorinated biphenyls, butanol enrichment generally showed a lower recovery. For some higher substituted congeners (3,3',4,4', 5-pentachloro-, 2,2',3,4,4',5'-hexachloro-, 2,2',4,4',5, 5'-hexachloro-, and 2,2',3,4,4',5,5'-heptachlorobiphenyl), after butanol enrichment a single dominant spot was observed, which was absent in the nuclease P1 procedure. After incubation of calf thymus DNA with either higher- or lower-chlorinated PCB congeners, we were not able to detect significantly increased levels of oxidative DNA damage above background levels, measured as 8-oxo-7, 8-dihydro-2'deoxyguanosine. In view of the carcinogenicity of PCB mixtures in animals and the ability of PCB metabolites to bind covalently to DNA, rats were orally treated with a mixture of PCBs (Aroclor 1242). PCB-DNA adduct levels were analyzed in PCB target organs: liver, thymus, glandular stomach, spleen, testes, seminal vesicles and prostate DNA. In vivo PCB-DNA adducts could not be detected by either the butanol- or by the NP1-enrichment procedure in rat target tissue DNA. Also, no differences in oxidative DNA damage could be observed between PCB-treated rats and controls. These results indicate a lack of DNA reactivity of PCB mixtures in vivo.
Environ Mol Mutagen 2000
PMID:Induction of DNA adducts by several polychlorinated biphenyls. 1101 5

Estrogens induce pronounced structural and functional changes in male accessory sex glands and the lower urinary tract in both sexes, but the exact mechanisms of estrogen action are not fully understood. This study was undertaken to localise the tissue cell types that express estrogen receptor in adult rats, and to determine the receptor subtype (ER alpha and ER beta) in order to identify sites that may respond directly to estrogens. In the male accessory sex glands (seminal vesicles, prostatic lobes and ampullary glands), ER beta mRNA and protein were strongly expressed in the epithelium but not in the stroma, while ER alpha mRNA was present only in the fibromuscular tissue surrounding the prostatic collecting ducts in the posterior periurethral region and in ampullary gland stroma. In the epithelium of the urinary bladder and urethra of both sexes, high level of ER beta mRNA and protein, but no ER alpha mRNA, was detected. The connective tissue in urinary bladder of both males and females, as well as that in prostatic urethra in males expressed ER alpha mRNA. The neural cells in the autonomic ganglia of the prostatic plexus were strongly positive for ER beta mRNA, but were completely devoid of ER alpha. We conclude that ER beta is the predominant ER subtype in the epithelium of adult male rat accessory sex glands and the lower urinary tract of both males and females, as well as in the prostatic neural plexus regulating the function of the lower urinary tract in males, while ER alpha is present only in the stromal compartment of distinct sites. These results indicate that in these tissues in intact adults there are multiple targets for direct estrogen action. Furthermore, the differential or complementary expression of the two ER subtypes suggests that they may have specific functions, and may explain the complex structural and functional changes induced by estrogens.
Mol Cell Endocrinol 2000 Jun
PMID:Differential expression of estrogen receptors alpha and beta in adult rat accessory sex glands and lower urinary tract. 1116 5

Oestrogen exposure of the male during fetal/neonatal life can fundamentally alter the structure and function of the reproductive system, though how is unknown. This study examined whether such treatment was able to induce a 'female' characteristic, namely immunoexpression of progesterone receptor (PR), in the reproductive system of the male. Rats were treated on postnatal days 2, 4, 6, 8, 10 and 12 with either 10, 1 or 0.1 microg diethystilbestrol (DES) or with the vehicle (20 microl corn oil). Groups of control and treated rats were killed on days 18, 25, 35 and 90 (= adults) and tissues fixed in Bouins for immunolocalisation studies using antisera to PR (recognises A and B forms) and oestrogen receptor-beta (ER beta). PR immunoexpression was absent from all tissues studied in control rats at all ages with the exception of the parasympathetic ganglia of the prostate. In rats treated with 10 microg DES, intense immunoexpression of PR was detected in the nuclei of stromal, but not epithelial, cells of the caput and cauda epididymis, the vas deferens, seminal vesicles and at the base of the dorsolateral prostatic complex (DLPC) at day 18, but was absent from the ventral prostate and from the testis. DES induction of PR immunoexpression was evident after a single injection (on day 3) and at 18-35 days the intensity of immunoexpression was DES dose-dependent; rats treated neonatally with 0.1 microg DES showed no detectable PR immunoexpression at any age. These findings were confirmed by Western analysis which indicated that most of the PR induced was probably the B form. Co-localisation studies, using confocal microscopy, demonstrated that PR and ER beta frequently co-localised to the same stromal cells in the DLPC, epididymis and seminal vesicles of DES-treated rats at day 18, whereas epithelial cells, which also expressed ER beta, did not express PR. In the tissues studied, only occasional stromal cells expressed ER alpha in comparison to the more widespread expression of ER beta, although epithelial cell expression of ER alpha was also detected in the epididymis on day 18 (but not on day 10). In DES-treated rats, immunoexpression of PR in the reproductive tract decreased progressively in intensity from days 18-35 and was non-detectable in adulthood. In conclusion, these findings are interpreted as evidence that neonatal oestrogen treatment exerts pervasive 'reprogramming' effects throughout the reproductive system of the developing male as indicated by the induction of PR immunoexpression. This induction was restricted to stromal tissue even though both stromal and epithelial cells at most sites expressed ER beta and/or ER alpha.
Mol Cell Endocrinol 2000 Jun
PMID:Induction of progesterone receptor immunoexpression in stromal tissue throughout the male reproductive tract after neonatal oestrogen treatment of rats. 1102 64

Although conventional ultrasonography has proven to be clinically useful for depicting many types of cancerous lesions, it cannot distinguish reliably between cancerous and noncancerous tissue of the prostate. Therefore, conventional transrectal ultrasonography (TRUS) is used primarily for general evaluations of the gland and for guiding biopsies based on clearly imaged anatomic features such as the capsule, seminal vesicles, and urethra. Spectrum analysis extracts ultrasound signal parameters associated with biopsy-proven tissue types, and these parameters are then classified using neural network tools such as learning vector quantization, radial basis, and multilayer perceptron algorithms. Classification of cancerous and noncancerous prostate tissue using neural networks produces receiver operating characteristic (ROC) curves of 0.87 +/- 0.04 compared with 0.64 +/- 0.04 for conventional ultrasonography. To image the prostate using these methods, parameter values are computed at each pixel location, then translated into a score for the likelihood of cancer using a look-up table generated using the best classification algorithm. The score for cancer likelihood is expressed as a gray-scale or color value, and the resulting image may be useful to guide biopsies or therapy. Changes in parameter or score values over time potentially can be used to assess progression of disease or efficacy of therapy.
Mol Urol 2000
PMID:Three-dimensional ultrasound analyses of the prostate. 1106 67

Estrogens induce pronounced structural and functional changes in male accessory sex glands and the lower urinary tract in both sexes, but the exact mechanisms of estrogen action are not fully understood. This study was undertaken to localise the tissue cell types that express estrogen receptor in adult rats, and to determine the receptor subtype (ERalpha and ERbeta) in order to identify sites that may respond directly to estrogens. In the male accessory sex glands (seminal vesicles, prostatic lobes and ampullary glands), ERbeta mRNA and protein were strongly expressed in the epithelium but not in the stroma, while ERalpha mRNA was present only in the fibromuscular tissue surrounding the prostatic collecting ducts in the posterior periurethral region and in ampullary gland stroma. In the epithelium of the urinary bladder and urethra of both sexes, high level of ERbeta mRNA and protein, but no ERalpha mRNA, was detected. The connective tissue in urinary bladder of both males and females, as well as that in prostatic urethra in males expressed ERalpha mRNA. The neural cells in the autonomic ganglia of the prostatic plexus were strongly positive for ERbeta mRNA, but were completely devoid of ERalpha. We conclude that ERbeta is the predominant ER subtype in the epithelium of adult male rat accessory sex glands and the lower urinary tract of both males and females, as well as in the prostatic neural plexus regulating the function of the lower urinary tract in males, while ERalpha is present only in the stromal compartment of distinct sites. These results indicate that in these tissues in intact adults there are multiple targets for direct estrogen action. Furthermore, the differential or complementary expression of the two ER subtypes suggests that they may have specific functions, and may explain the complex structural and functional changes induced by estrogens.
Mol Cell Endocrinol 2000 Dec 22
PMID:Differential expression of estrogen receptors alpha and beta in adult rat accessory sex glands and lower urinary tract. 1102 63

Presence or absence of three distinct bovine seminal heparin-binding proteins (21-31 kDa) recognized in sperm extracts by a monoclonal antibody, M1, is a diagnostic indicator of fertility differences among bulls producing normal semen. We recently identified a 31 kDa fertility-associated antigenin bovine seminal fluid as a unique DNase I-like protein. We now report purification and identification of a 24 kDa seminal heparin-binding protein (HBP-24) recognized by M1. N-terminal microsequence analysis of HBP-24 purified from seminal fluid yielded 20 amino acid residues that displayed 90% identity to the N-terminus of a bovine metalloproteinase inhibitor identified as tissue inhibitor of metalloproteinases-2 (TIMP-2). A single immunoreactive band migrating at 24 kDa was detected in Western blots of cauda epididymal sperm extracts following incubation with purified seminal heparin-binding proteins and subsequent washing in vitro, indicating TIMP-2 bound to sperm membranes. Expression of TIMP-2 mRNA was detected by RT-PCR in bovine bulbourethral gland, prostate, and seminal vesicles. Mobility of the 24 kDa heparin-binding protein increased under nonreducing SDS-PAGE to approximately 21 kDa, characteristic of the reported molecular mass of TIMP-2. To our knowledge, this is the first report of TIMP-2 binding to spermatozoa and of TIMP-2 mRNA expression in bovine accessory sex glands. These results corroborate previous reports regarding the site of production of heparin-binding proteins that are related to bull fertility, and suggest that TIMP-2 influences fertility of bulls, either through inhibition of metalloprotease activity in semen or via undefined activities independent of matrix metalloproteinase (MMP) inhibition.
Mol Reprod Dev 2001 Mar
PMID:Identification of a heparin-binding protein in bovine seminal fluid as tissue inhibitor of metalloproteinases-2. 1117 Feb 75

One of the dramatic changes in the prostate during androgen manipulation is the alteration in cellular content of total RNA - the amount of total RNA in each cell. The abundance of cellular total RNA correlates with the RNA polymerase (RNAP) activity in the prostate. One possible mechanism of androgen regulation of RNAP activity involves the regulation of RNAP expression. Western blot analysis showed that the largest subunit of the RNAP II, an essential component of the transcriptional machinery for mRNA, is indeed regulated by androgens. Castration down-regulates the protein level of RNAP II, whereas androgen replacement up-regulates the protein. However, androgen manipulation does not have consistent effects on the phosphorylation of the C-terminal domain (CTD) of the RNAP II. Androgen regulation of the RNAP II protein expression was also observed in the seminal vesicles but not in the thymus and liver, indicating that androgen regulation of RNAP II protein expression appears to be limited to the male sex accessory organs. These observations suggest that RNAP II plays an essential role in androgen action in male sex accessory organs.
J Steroid Biochem Mol Biol 2000 Dec 01
PMID:Androgen regulation of the largest subunit of RNA polymerase II in the rat ventral prostate. 1117 7


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