Estrogen-induced microvilli and microvillar channels and entrapment of surfactant-lipids by alveolar type I cells of bovine lung.
(49/2065)
The ATI cells are simple, flat squamous epithelial cells, which are evolved to function as a component of the alveolar-capillary membrane, ideally designed for gaseous exchange. They inherently lack an active metabolic machinery and lead a precarious existence in the face of hostile environment. On the other hand, the ATI cells of the lung of ruminating animals are endowed with structure-functional properties which enable them to exert a selective barrier function against a wide range of osmotic pressure gradients at their luminal surface. Such gradients are created by a complex gaseous homeostasis due to expectoration of several gases and volatile fatty acids originating from the complex stomach of the ruminants. The purpose of this study is to examine the effect of estradiol propionate on the ultrastructure of the ATI cells and their interaction with the surfactant lipids. The lungs of estrogen and dexamethasone treated male calves were harvested for electromicroscopic examination. The evidence is presented that estradiol induced the formation of microvilli and microvillar channels at the luminal surface. At these regional modifications, intense interactions with the surfactant lipids and their entrapment into the pathways of endocytosis, took place in the squamous part of the ATI cells. Concurrently, large basal protrusions ended up as long lamellipods deep into the alveolar interstitium. The filamentous cytoskeletal network and microtubules intermixed with the translocated organelles such as Golgi apparatus and associated coated and uncoated vesicles. The results of this study support the hypothesis that estrogen regulate the selective barrier-function of the ATI cells. The entrapment of surfactant lipids under the influence of estrogen by ATI cells is a significant change perhaps in response to extracellular stimuli and expression of transmembrane receptors. It implies that these epithelial cells are specially evolved to adapt to a complex gaseous homeostasis in the lung of the ruminating ungulates. (+info)
Progression to androgen independence is delayed by adjuvant treatment with antisense Bcl-2 oligodeoxynucleotides after castration in the LNCaP prostate tumor model.
(50/2065)
Bcl-2 has emerged as a critical regulator of apoptosis in a variety of cell systems and is up-regulated during progression to androgen independence in prostate cancer cells. The objectives of this study were to characterize changes in Bcl-2 after androgen withdrawal and during progression to androgen independence in the human prostate LNCaP tumor model and determine whether adjuvant use of antisense Bcl-2 oligodeoxynucleotides (ODNs) with androgen ablation delays progression to androgen independence. Bcl-2 expression in LNCaP cells is down-regulated to undetectable levels by androgen in vitro and up-regulated after castration in vivo. Antisense Bcl-2 ODN treatment reduced LNCaP cell Bcl-2 messenger RNA and protein levels by >90% in a sequence-specific and dose-dependent manner at concentrations >50 nM. Bcl-2 mRNA levels returned to pretreatment levels by 48 h after discontinuing treatment. Athymic male mice bearing SQ LNCaP tumors were castrated and injected i.p. with 12.5 mg/kg/day with two-base mismatch ODN control, reverse polarity ODN control, or antisense Bcl-2 ODN. Tumor volume in control mice gradually increased 5-fold (range, 3-6) by 12 weeks after castration compared to a 10-50% decrease in precastrate tumor volume in mice treated with antisense Bcl-2 ODN. Changes in serum PSA paralleled changes in tumor volume, increasing 4-fold faster above nadir in controls than in mice treated with antisense Bcl-2 ODN. After decreasing 70% by 1 week after castration, PSA increased 1.6-fold above precastrate levels by 11 weeks in controls while staying 30% below precastrate levels in antisense-treated mice. In a second group of experiments, LNCaP tumor growth and serum PSA levels were 90% lower (P<0.01) in mice treated with antisense Bcl-2 ODN compared with mismatch or reverse polarity ODN controls. These results support the hypothesis that Bcl-2 helps mediate progression to androgen independence and is an appropriate target for antisense therapy. (+info)
A potential apulsatile mode of GnRH release in the male rhesus monkey (Macaca mulatta).
(51/2065)
The hypothalamic component of the reproductive axis in vertebrates is comprised of a pulse generator that stimulates the release of GnRH. Several lines of evidence are in agreement that the activity of this pulse generator is intermittent and results in the pulsatile pattern of GnRH and LH release. During a recent investigation of the re-initiation of LH secretion in the agonadal, prepubertal male monkey, we observed a daytime profile of LH secretion, which suggests an apulsatile mode of GnRH release. The first purpose of this study was to describe this observation of apulsatile LH release during the peripubertal transition. Furthermore, we have explored the dependence of this form of LH secretion on GnRH release. Five male rhesus monkeys (Macaca mulatta) were castrated prepubertally and were treated with an intermittent infusion of GnRH to prematurely sensitize the juvenile pituitary to endogenous GnRH release. Alternate daytime (1100-1800 h) and nighttime (1900-0200 h) assessments of LH release were performed at 10-day intervals throughout the peripubertal transition with samples taken every 12 min. In a second experiment, four agonadal males which demonstrated an apulsatile profile of LH release were maintained on an infusion of physiological saline and were treated with the GnRH antagonist Nal-Glu (i.m., 500 microgram/kg). Circulating levels of LH were determined 22 h after antagonist treatment. In peripubertal animals, circulating levels of LH were similar between morning and evening assessments. However, pulse frequency was significantly lower during the daytime. GnRH antagonist reduced LH levels by 72% and a similar reduction in response to an exogenous GnRH test stimulus occurred. These findings suggest an apulsatile mode of GnRH release. (+info)
Postnatal development and regulation of proteins secreted in the boar epididymis.
(52/2065)
The number of proteins secreted by the boar epididymis increased progressively from 1 mo of age to the adult period. The first specific secretory activity was revealed at 2 mo in the distal caput (hexosaminidase, clusterin, and lactoferrin) and in the corpus (train O/HE1). Train A and glutathione peroxidase specific to the proximal caput, and trains E and M specific to the corpus, appeared at 4 mo. At 5 mo, secretion of procathepsin L occurred in the middle caput and that of mannosidase and E-RABP in the distal caput. Approximately 48% of all the proteins secreted in the adult boar epididymis were dependent on the presence of androgens, either stimulated (33.6%) or repressed (14.4%); 47% were modulated by other factors, and 5% were unregulated. In the proximal caput, 50% of the specific secreted proteins were controlled essentially by factors emanating from the testis. In more distal regions, two proteins secreted in the corpus were regulated by factors from the anterior regions. The regionalization of the secretory activity of the epididymal epithelium resulted in a specific regulation for each protein, which was modulated according to the region of expression and influenced by either testicular or epididymal factors that remain to be identified. (+info)
Androgen deprivation facilitates acetylcholine-induced relaxation by superoxide anion generation.
(53/2065)
The aim of the present study was to assess the role of superoxide anions in the relaxation induced by acetylcholine (ACh) in aortic segments from male rats, and to investigate if their production is altered by sex hormone deprivation. In segments precontracted with 10 nmol/l noradrenaline, ACh (0.1 nmol/l-10 micromol/l) induced concentration-dependent relaxation, which was greater in segments from castrated compared with control animals. ACh-induced relaxation was abolished in segments from control rats, and reduced in those from castrated rats, by 0.1 mmol/l N(G)-nitro-L-arginine methyl ester (L-NAME; a nitric oxide synthase inhibitor). Indomethacin (1 micromol/l; a cyclo-oxygenase blocker) decreased the ACh-induced relaxation in arteries from control males only. Incubation of segments with superoxide dismutase (SOD; 100 units/ml; a superoxide anion scavenger) enhanced and reduced relaxation in segments from control and castrated animals respectively. For arteries from castrated animals, the presence of SOD plus L-NAME abolished such responses. In these arteries, incubation with L-NAME abolished the relaxation caused by ACh when the segments were precontracted with 30 mmol/l KCl. In segments obtained from castrated rats and pretreated with L-NAME, 1 mmol/l tetraethylammonium or 0.4 micromol/l charybdotoxin [blockers of Ca(2+)-sensitive and large-conductance Ca(2+)-sensitive (BK(Ca)) K(+) channels respectively] abolished the relaxation induced by ACh. These results suggest that ACh generates endothelial NO and superoxide anions from the arterial wall in both control and castrated animals; these agents negatively modulate ACh-induced relaxation in control rats by destruction of NO, and positively modulate ACh-induced relaxation in castrated rats by activation of BK(Ca) channels. (+info)
Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer.
(54/2065)
BACKGROUND: Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy. METHODS: Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually. RESULTS: After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome. CONCLUSIONS: Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer. (+info)
Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles.
(55/2065)
The effects of castration and dihydrotestosterone (DHT) treatment on levels of skeletal muscle androgen receptor (AR) were examined in three groups of adult male rats: 1) intact normal rats, 2) rats castrated at 16 wk of age, and 3) rats castrated at 16 wk of age and given DHT for 1 wk starting at week 17. All animals were killed at 18 wk of age. Castration caused a decrease (P < 0.05) in the weights of the levator ani and bulbocavernosus muscles. The administration of DHT to the castrated rats increased (P < 0.05) the weights of the levator ani and bulbocavernosus muscles. Castration caused a significant downregulation of AR levels in the bulbocavernosus (P < 0.05) but had no significant effect on AR levels in the levator ani muscle. DHT administration to the castrated group upregulated AR levels in the bulbocavernosus and levator ani muscles. The plantaris muscle did not significantly (P > 0.05) change for any of the treatments. These findings suggest that the effects of castration and androgen replacement differentially affect skeletal muscle mass and AR levels. (+info)
The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis.
(56/2065)
BACKGROUND: The Fas ligand/Fas receptor (FasL/Fas) system is an important mediator of apoptosis in the immune system where the juxtaposition of cells expressing the cell-surface ligand induces the apoptotic pathway in Fas-expressing lymphocytes. The FasL/Fas system has also been shown to be involved in apoptosis in epithelial tissues, including the involuting rodent prostate. FasL can be shed through the action of an hitherto unidentified metalloproteinase to yield soluble FasL (sFasL), although the biological activity of sFasL has been disputed. RESULTS: Here we report that the matrix metalloproteinase matrilysin can process recombinant and cell-associated FasL to sFasL, and that matrilysin-generated sFasL was effective at inducing apoptosis in a target epithelial cell population. In the involuting mouse prostate, FasL and matrilysin colocalized to the cell surface in a restricted population of epithelial cells. Mice deficient in matrilysin demonstrated a 67% reduction in the apoptotic index in the involuting prostate compared with wild-type animals, implicating matrilysin in this FasL-mediated process. CONCLUSIONS: The results show that a functional form of sFasL was generated by the action of the metalloproteinase matrilysin, and suggest that matrilysin cleavage of FasL is an important mediator of epithelial cell apoptosis. (+info)