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Biomedical subjects

Seijiro Honma

Publications and source records attributed to Seijiro Honma.

13 recordsLinked to original sources
PubMed2006

Positive effect of prostaglandin on regulation of prostatic blood flow.

OBJECTIVES: To investigate the effects of prostaglandin E2 (PGE2) and its antireceptor antibody on prostatic blood flow regulation using a rat model. We estimated that PGE2 participated in the signaling pathway of hormonal regulation of the prostatic blood flow. METHODS: The rats were castrated and injected locally with dihydrotestosterone (200 ng/head) or PGE2 (250 ng/head) directly into the prostatic membrane. After local dihydrotestosterone or PGE2 administration, anti-PGE2 receptor antibody (200 ng/head) was injected locally to investigate interruption of the signaling pathway. After administration, we evaluated the relative prostatic blood flow using a laser blood flow meter. The change in cyclooxgenase-2 mRNA expression and the changes in PGE2 concentration in response to androgen stimulation were also examined. RESULTS: PGE2 was involved in blood flow regulation with activity equal to that of androgen. The effect of dihydrotestosterone was abolished by coadministration with anti-PGE2 receptor antibody. Cyclooxgenase-2 gene expression was upregulated in response to androgen stimulation. The PGE2 concentration also increased in response to androgen stimulation. CONCLUSIONS: Our finding of PGE2 participation in androgen regulation of prostatic blood flow might lead to pathophysiologic elucidation of prostatic diseases.

Animals↗
PubMed2006

Participation of adrenomedullin and its relation with vascular endothelial growth factor in androgen regulation of prostatic blood flow in vivo.

OBJECTIVES: We had previously reported that androgen-regulated prostatic blood flow and vascular endothelial growth factor (VEGF) were involved in the signal transduction pathway. Adrenomedullin (ADM) is a multifunctional regulatory peptide with mitogenic and angiogenic capabilities that are regulated by androgen. ADM is abundantly expressed in the prostate. We focused on ADM and evaluated its participation and relation with VEGF in androgen prostatic blood flow regulation using a castrated rat model. METHODS: We examined the effect of locally injected dihydrotestosterone (DHT) and ADM, and the co-administration of DHT with an ADM receptor antagonist (ADM 22-52) on prostatic blood flow. Furthermore, prostatic blood flow was evaluated after ADM and VEGF administration with each other's antagonist, VEGF neutralizing antibody and ADM 22-52, respectively. Changes in the mRNA expression levels of ADM in the prostate after castration and successive androgen stimulation were also evaluated. RESULTS: The administration of ADM promptly increased prostatic blood flow in a dose-dependent manner within 30 minutes. The DHT-induced increase in prostatic blood flow was completely abolished by co-administration with anti-ADM. Anti-ADM inhibited the VEGF-induced prostatic blood flow elevation, but a VEGF neutralizing antibody did not affect the ADM-mediated blood flow elevation. Furthermore, upregulation of the ADM gene induced by DHT was inhibited by co-administration with a VEGF-neutralizing antibody. CONCLUSIONS: These results have clearly demonstrated the direct regulation of prostatic blood flow by ADM and its involvement in androgenic prostatic blood flow regulation. Furthermore, ADM was estimated to be a downstream mediator of VEGF action in the signal transduction pathway.

Adrenomedullin↗
PubMed2005

Deletion of macrophage migration inhibitory factor gene induces down regulation of sex hormones and ultrastructural abnormalities in mouse testes.

Macrophage migration inhibitory factor (MIF) is a multifunctional protein that acts as a pro-inflammatory cytokine, pituitary hormone, immunoregulator and mitogen. The MIF gene knockout (MIFKO) mouse has been used to study the MIF response in many tissues, such as with skin injury and spinal cord injury; however, there is little information about the MIFKO mouse testis. This study reports the levels of serum and intratesticular estradiol and testosterone, the ultrastructure of the testis, and preliminary findings from in vitro fertilization. Our results revealed a decrease in estradiol and testosterone levels and deformation in spermiogenesis, in the MIFKO mouse. These initial findings study may lead to a better understanding of the role that MIF plays in the mouse testis.

Animals↗
PubMed2005

Determination of sulfates of androsterone and epiandrosterone in human serum using isotope diluted liquid chromatography-electrospray ionization-mass spectrometry.

A promising liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) for analysis of the sulfates of 5alpha-androgen, androsterone and epiandrosterone (A-S and EpiA-S) in human serum was developed. The method was used to assess one of the markers of 5alpha-reductase activity of males including patients with prostate cancer (PC). After deproteinization with acetonitrile, the androgen sulfates and the internal standard, [7,7,16,16-2H4]dehydroepiandrosterone-S, were extracted from human serum using a solid-phase extraction cartridge and washed with hexane. The extract was reconstituted and applied to the LC/ESI-MS system operated in the selected ion monitoring mode. The method was validated over the range 0.02-5 microg/mL (A-S) and 0.005-1.5 microg/mL (EpiA-S) using 10 microL of human serum. The method was a concise procedure without chemical or enzymatic hydrolysis of the conjugates, purification by high-performance liquid chromatography and/or derivatization, and proved to be satisfactory in its reproducibility and accuracy. The levels of these androgen sulfates tended to decrease during aging, and the A-S levels in the sera obtained from both healthy males and patients with PC were correlated with their EpiA-S levels.

Adult↗
PubMed2005

Effect of androgen concentration on seminal vesicle blood flow in rats-establishment of new highly sensitive simultaneous androgen measurement method.

OBJECTIVES: To clarify the effect of androgen concentration on blood flow regulation in seminal vesicles and to identify the androgen most responsible for this effect. METHODS: The androgen concentrations in the seminal vesicles and the seminal vesicle blood flow were measured at 0, 3, 6, 12, 24, 48, and 72 hours after castration. The androgen concentration was measured with a newly developed highly sensitive simultaneous androgen quantification method that uses liquid chromatography-tandem mass spectrometry. The blood flow was measured with the radioactive microsphere injection method. The change in seminal vesicle blood flow in 6-hour castrated rats after administration of 3 mg/kg testosterone, 3 mg/kg dihydrotestosterone (DHT), 3 mg/kg dehydroepiandrosterone, or 3 mg/kg testosterone plus 20 mg/kg finasteride was evaluated. RESULTS: A correlation was observed between the DHT concentration and blood flow in the rat seminal vesicle after castration. The DHT concentration and blood flow decreased after castration to 31.6% and 37.9%, respectively, of the normal level at 6 hours. The decline in DHT concentration and blood flow decreased further thereafter to 2.2% and 18.1%, respectively, of the normal level at 72 hours. Both testosterone and DHT fully restored the organ blood flow in castrated rat seminal vesicles. However, the blood-flow-increasing effect of testosterone was attenuated by more than 50% when administered in combination with finasteride. Dehydroepiandrosterone did not increase seminal vesicle blood flow. CONCLUSIONS: The results of our study showed a strong correlation between the organ DHT concentration and blood flow in rat seminal vesicles. Of the various androgens, the most active androgen in the regulation of seminal vesicle blood flow was DHT.

Androgens↗
PubMed2004

Direct regulation of prostate blood flow by vascular endothelial growth factor and its participation in the androgenic regulation of prostate blood flow in vivo.

Previous studies on prostate blood flow regulation have indicated that androgen regulates prostate blood flow. However, the mechanism responsible for this regulation is unknown. In the present study, we focused on the effects of vascular endothelial growth factor (VEGF), a key factor responsible for angiogenesis and androgenic blood flow regulation. We examined in vivo the effect of VEGF on prostate blood flow and its participation in the androgenic regulation of this blood flow using a castrated rat model following subcapsular intraprostatic injection method. We found that VEGF is involved in blood flow regulation with an activity equal to that of dihydrotestosterone (DHT). The effect of VEGF on prostate blood flow was already seen at 30 min after the administration. The elevating effect of DHT on castrated rat prostate blood flow was abolished by coadministration of DHT with neutralizing anti-VEGF antibody. The change in VEGF-A mRNA expression in response to androgen stimulation was examined by double-fluorescent probe quantitative PCR (Taqman PCR). The results showed that androgenic regulation of VEGF gene expression occurred shortly after androgen stimulation. VEGF gene up-regulation was abolished or down-regulated by coadministration of neutralizing anti-VEGF antibody. This is the first report on the importance of VEGF in the androgenic regulation signaling pathway that affects prostate blood flow. Alternative treatment targeted toward anti-VEGF activity as a substitute for ordinary antiandrogenic therapy may be effective against prostate diseases, especially those with androgen-independent and hyperhemorrhagic status.

Androgens↗
PubMed2004

The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor.

Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR's association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.

Androgen Antagonists↗
PubMed2003

Simultaneous determination of androstenediol 3-sulfate and dehydroepiandrosterone sulfate in human serum using isotope diluted liquid chromatography-electrospray ionization-mass spectrometry.

A simple method for simultaneous determination of androstenediol 3-sulfate (Adiol-3S) and dehydroepiandrosterone sulfate (DHEA-S) in human serum using isotope diluted liquid chromatography-electrospray ionization-ion trap-mass spectrometry (LC-ESI-ion trap-MS) was developed. After addition of deuterated internal standards ([2H5]Adiol-3S and [2H4]DHEA-S), human serum (100 microl) was deproteinized with acetonitrile and then applied to a solid-phase extraction cartridge, Oasis HLB. The obtained steroid sulfates fraction was washed with hexane and then analyzed by LC-ESI-MS operated in the negative ion mode. The quantification ranges of Adiol-3S and DHEA-S were 10-400 ng/ml and 0.05-8 microg/ml, respectively. The method does not require the chemical or enzymatic hydrolysis of the conjugates and purification with high-performance liquid chromatography, and shows satisfactory reproducibility and accuracy. The concentrations of these sulfates in the sera of healthy male volunteers (n=14) were 19.2-245.3 mg/ml (Adiol-3S) and 0.175-5.16 microg/ml (DHEA-S), and those of patients with prostate cancer (n=19) were 15.3-182.7 ng/ml (Adiol-3S; four samples, not detectable) and 0.110-2.421 microg/ml (DHEA-S).

Aged↗
PubMed2003

The evaluation of rat prostate blood flow using a laser speckle flowmetry: a comparative study using the microsphere method in castrated and androgen-replenished rats.

To evaluate the accuracy and reliability of laser speckle blood flowmetry in the measurement of prostate blood flow, we performed a comparative study with the ordinary intra-arterial radioactive microsphere injection method using the well-known castrate-rat model. Adult male Wistar strain rats were used for the study. The rats were either only castrated or subcutaneous testosterone replenishment was followed subcutaneously 6 h after castration. The prostate blood flow was measured at different time courses after castration. The effect of a single androgen replenishment on prostate blood flow was also evaluated. The measurement of prostate blood flow was performed by both the radioactive microsphere injection method and laser speckle blood flowmetry, and then the outcomes were compared. Rapid reduction in prostate blood flow to 30% of the normal level was observed 24 h after castration in the measurements with the microsphere injection technique. The prostate blood flow decreased gradually after 24 h post-castration to 23 and 21% of the normal level at 48 and 72 h after castration, respectively. The laser speckle blood flowmetry also detected the decrease in prostate blood flow well, but in a more gradual manner. The prostate blood flow was 70, 52 and 35% of the normal level at 24, 48 and 72 h after castration, respectively. The effect of a single administration of testosterone to castrated rats had recovered the prostate blood flow to 74 and 98% of the normal level by measurement with the microsphere injection technique and laser speckle blood flowmetry, respectively. The different outcome in blood flow rate change between the methods can be explained according to their different mechanism of measurement, thus suggesting the capillary vessels are the early and most responsive portion for hormonal manipulation. In conclusion, the laser speckle blood flowmetry is a convenient and reliable method for evaluating prostate blood flow, especially when the organ is required for other biological and molecular assays, since the method does not require the excision of the organ for the measurement.

Androgens↗
PubMed2003

Hormonal and morphologic evaluation of the effects of antiandrogens on the blood supply of the rat prostate.

OBJECTIVES: To clarify the basic aspects of the regulation of the prostatic blood supply by antiandrogens, their effect on the prostatic blood supply was studied for both androgen content and morphology of true capillaries in the rat ventral prostate. The effectiveness of antiandrogens on the control of hemorrhagic status in prostatic diseases has been previously reported. METHODS: Androgen concentrations in the prostate were quantified after administration of chlormadinone acetate (CMA), finasteride, or flutamide. The prostatic blood supplies were measured after administration of CMA, finasteride, flutamide, or bicalutamide. The alpha-blockers, terazosin and tamsulosin, were included in the study as negative controls. The histologic changes in the capillaries of the ventral prostate were observed, and the luminal area was measured. RESULTS: The prostate dihydrotestosterone concentrations were decreased by the administration of all antiandrogens. Treatment with CMA, finasteride, flutamide, or bicalutamide reduced the prostatic blood supply by 50% to 65%. The parallel reduction in luminal areas of the true capillaries was observed in rats treated with CMA. Treatment with alpha-blockers did not affect the prostate androgen content, prostatic blood supply, or capillary luminal area. CONCLUSIONS: The reduction of the prostatic blood supply was suggested to be the result of a decrease in dihydrotestosterone content and the reduction in the luminal area of capillaries. The early reductive effect of antiandrogens on the prostatic blood supply suggests an alternative use for antiandrogens independent of their typical use for prostate volume regression. The results support the basic aspects of the advantage of preoperative treatment with CMA, flutamide, and bicalutamide, similar to finasteride, in reducing perioperative hemorrhage.

5-alpha Reductase Inhibitors↗
PubMed2002

Identification of dehydroepiandrosterone metabolites formed from human prostate homogenate using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry.

The identification of the in vitro metabolites of dehydroepiandrosterone formed from human prostate homogenate was investigated by hyphenated techniques using the stable-isotope dilution method. A mixture of dehydroepiandrosterone and [2H4]dehydroepiandrosterone was incubated with hypertrophied human prostate tissue homogenate in the presence of NAD, NADH and NADPH. The metabolites were extracted with AcOEt-hexane, purified by solid-phase extraction, and then analyzed by LC-atmospheric pressure chemical ionization MS and/or GC-MS. Androst-5-ene-3beta,17beta-diol (major product), androst-4-ene-3,17-dione, testosterone, 5alpha-dihydrotestosterone, androsterone, and 7alpha-hydroxydehydroepiandrosterone were identified in comparison with authentic samples based on their chromatographic behavior and mass spectra.

Chromatography, Gas↗
PubMedDate not supplied

Changes in testosterone and dihydrotestosterone levels in male rat accessory sex organs, serum, and seminal fluid after castration: establishment of a new highly sensitive simultaneous androgen measurement method.

It is known that abnormal androgen dynamics in the tissues is a cause of androgen-dependent disorders. Investigation of tissue androgen levels could provide a clue to the elucidation of disorders. However, it is difficult to measure a trace amount of androgen in the tissues. We established a highly sensitive simultaneous quantification method of testosterone and dihydrotestosterone (DHT), which play the most important roles in the body among androgenic steroids in trace amounts, and investigated time course changes in testosterone and DHT levels in male accessory sex organs, serum, and seminal fluid after castration in rat models. In addition, changes in the testosterone/DHT ratio of male accessory sex organs and seminal fluid were observed. The simultaneous testosterone and DHT measurement method established by us was validated. Intra-assay variation and interassay precision and accuracy were all within +/-20%, and the quantification limits of testosterone and DHT were both 15.6 pg/g. With the use of this method, the testosterone and DHT levels in the prostate, seminal vesicles, and serum immediately after castration were similar to those previously reported. The testosterone and DHT levels were 350 pg/g and 605 pg/g, respectively; which showed dominance of DHT in seminal fluid, although it was not as marked as that in the male accessory sex organs. Androgens decreased with time after castration in the accessory sex organs, serum, and seminal fluid. In the prostate and seminal vesicles, testosterone and DHT decreased to about 50% and about 2% of the normal levels, respectively, 72 hours after castration. The serum levels were under the quantification limits 6 hours after castration and thereafter. In seminal fluid, the testosterone and DHT levels decreased to 49% and 35% of normal levels, respectively, 72 hours after castration. The testosterone/DHT ratio in the male accessory sex organs was lower in the prostate (0.06) than in the seminal vesicles (0.13) immediately after castration. In the seminal fluid, changes in the ratio were small compared with those in the accessory sex organs and serum. These results showed that our method was capable of measuring testosterone and DHT in very small amounts of samples such as prostate biopsy specimens, and it might provide a clue to the elucidation of the pathology of androgen-dependent disorders.

Animals↗