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Journal Article 2002; 23(Suppl 1): 24-29 PubMed PMID: 12019348 Citation  Keywords:  Animals, Antineoplastic Agents:pharmacology, Humans, Melatonin:pharmacology, Neoplasms:drug therapy, Neoplasms, Experimental:drug therapy,.   

: The paper presents the data concerning the in vivo effects of melatonin on experimentally-induced tumors in animals and the in vitro effects on animal and human tumor cells. The majority of experimental tumors responded to the melatonin treatment with growth inhibition. However, some negative or opposite results (i.e. stimulation of tumor instead of inhibition) were also reported. Some of the negative results can be attributed to the improper timing of melatonin administration. Melatonin was also shown to inhibit the growth of several animal and human tumor cell lines in vitro. On the basis of these experiments, a hypothesis of the oncostatic action of melatonin was put forward. The mechanism of the postulated action is complex and probably includes: 1) modulation of the endocrine system; 2) modulation of the immune system; 3) the direct oncostatic action of melatonin on tumor cells. The latter includes the recently discovered anti-oxidative action which probably plays an important role in the countering the DNA damage during the radiation challenge or the exposure to chemical carcinogens. It also includes the antiproliferative and pro-apoptotic effects exerted via melatonin receptors expressed by tumor cells. The involvement of the membrane melatonin receptors is mainly assumed. However, the recent data from our and other laboratories suggest also the involvement of RZR/ROR receptors (the putative melatonin nuclear receptors) in both melatonin-induced proliferation inhibition and apoptosis....

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Clinical Trial 2002; 23(Suppl 1): 17-19 PubMed PMID: 12019346 Citation  Keywords:  Aged, Aged, 80 and over, Antioxidants:pharmacology, Blood Cell Count, Dehydroepiandrosterone Sulfate:blood, Estradiol:blood, Female, Humans, Hydrocortisone:blood, Melatonin:pharmacology, Pilot Projects, Sleep:drug effects, Sleep Wake Disorders:drug therap.   

OBJECTIVES: The role of melatonin is aging is still under debate. Therefore, an open pilot study on the effects of melatonin administration on some sleep parameters, routine hematological and biochemical parameters, and concentrations of hormones was performed in elderly women.

SUBJECTS AND METHODS: The study was performed on 14 women (volunteers), aged from 64 to 80 years (mean age 71+/-4.6 years). Melatonin (2 mg daily at 19:00 h) was administered during 6 months. Before and after melatonin treatment the peripheral venous blood samples were taken in the morning (approx. at 08:00 h) after the overnight fast. The total blood count, glucose, total cholesterol, LDL, HDL, and triglycerides were estimated by routine laboratory methods. The serum concentrations of the following hormones were determined: 17-beta-estradiol, dehydroepiandrosterone sulfate (DHEAS), cortisol, and somatomedin C (IGF-I). Additionally, before and after 6 months of melatonin therapy the investigated subjects answered to a questionnaire dealing with sleep parameters and self-estimation of general health status.

RESULTS: In 35.7% of investigated subjects an improvement in general sleep quality and in such sleep parameters as sleep initiation, sleep latency, number of awakenings episodes, wake time after sleep onset, was observed. A significant decrease of estradiol concentrations was observed after 6 months of the melatonin treatment in comparison to initial levels. IGF-I was found to be slightly but significantly increased after the 6 months melatonin therapy. Cortisol levels did not change significantly, during the melatonin treatment. DHEAS concentrations increased after melatonin therapy. Moreover, a tendency towards a higher DHEAS/cortisol ratio was found after 6 months of treatment. Melatonin treatment did not influence significantly either the parameters of total blood count or glucose and serum lipids levels.

CONCLUSIONS: On the basis of this preliminary open study it seems that melatonin administration may be beneficial for elderly subjects....

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Journal Article 2002; 23(Suppl 1): 14-16 PubMed PMID: 12019345 Citation  Keywords:  Aging:physiology, Animals, Circadian Rhythm:physiology, Humans, Melatonin:physiology, Pineal Gland:physiology,.   

: Although many theories relating the pineal secretory product melatonin to aging have been put forward, the role of this agent in the aging process is not clear. However, there are several reasons to postulate a role for melatonin in this process. Melatonin levels fall gradually over the life-span. Melatonin is a potent free radical scavenger. Melatonin deficiency is related to suppressed immunocompetence. In at least one animal model melatonin supplementation increased life-span although several other studies have failed. The aging process is multifactorial, and no single element seems to be of basic importance. It seems, however, that although melatonin can not be univocally recognized as a substance delaying aging, some of its actions may be beneficial for the process of aging. However, the precise role of melatonin in the aging process remains to be determined....

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Journal Article 2002; 23(2): 170-187 PubMed PMID: 12011804 Citation  Keywords:  Authorship, Humans, Neuroendocrinology:trends, Neuroimmunomodulation, Periodicals as Topic:trends,.   

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Journal Article 2002; 23(2): 161-167 PubMed PMID: 12011803 Citation  Keywords:  Analgesics, Opioid:pharmacology, Animals, Behavior, Animal:drug effects, Chickens, Dose-Response Relationship, Drug, Female, Immune System:drug effects, Irritants, Leukocyte Count, Leukocytes:cytology, Male, Morphine:pharmacology, Peritoneum:cytology, Per.   

BACKGROUND: Morphine exerts immunomodulatory effects dependent on several factors including species and parameter examined. The aim of this study was to assess the influence of morphine on experimental peritonitis and leukocyte activity in young chickens of both sexes.

METHODS: Peritonitis was elicited by intraperitoneal injection of thioglycollate (TG) alone or supplemented with morphine; additional chicken groups were injected with morphine alone. Morphine-treated birds (with or without elicited peritonitis) were pretreated with naltrexone, an antagonist of opioid receptors. Control groups were intact or PBS-injected. At specific postinjection intervals peritoneal leukocytes (PTL) were obtained by flushing the peritoneal cavity, counted and used for in vitro assays of activity (respiratory burst). Vascular permeability was measured using Evans blue solution.

RESULTS: Inflammatory reaction and morphine influence were gender-dependent: the extent of TG-induced peritonitis was higher in males and it was additionally stimulated by morphine. This pro-inflammatory effect of morphine was not seen in females. PTL collected from morphine-treated chickens of both sexes exhibited a stronger nitroblue tetrazolium reduction than in non-treated birds and this effect was antagonized by naltrexone.

CONCLUSIONS: The effect of morphine on peritonitis in chickens appears different to that in other vertebrate species, although the mechanism(s) of its influence on leukocyte activity are similar....

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Journal Article 2002; 23(2): 155-160 PubMed PMID: 12011802 Citation  Keywords:  Aged, Aged, 80 and over, Alzheimer Disease:blood, Estradiol:blood, Estrone:blood, Female, Folic Acid:blood, Humans, Logistic Models, Mental Status Schedule, Testosterone:blood,.   

OBJECTIVES: In vitro and in vivo animal studies suggest that sex steroids, such as estrogens and testosterone, could protect the brain. However, estrogen replacement therapy (ERT) for Alzheimer's disease (AD) in women has not been successful. We hypothesised that the lack of effect of ERT might be related to an interaction between estrogens and some other factor(s) associated with AD.

DESIGN, SETTING AND METHODS: We analysed total estrogen (TE) and testosterone (TT) levels in women diagnosed with AD and controls of the Oxford Project To Investigate Memory and Ageing. Because estradiol (TE2) after the menopause is largely derived from estrone (TE1), we computed the ratio TE2/(TE1+TE2) and a total steroid index (TT+TE2+TE1).

RESULTS: Women with AD (n=66) had significantly higher levels of TE2 (27+/-13 vs. 21+/-13) and a higher TE2/(TE1+TE2) ratio. Stepwise logistic regression analyses showed that the TE2/(TE1+TE2) ratio was the main sex steroid predictor for AD (O.R.=1.06, 95% C.I.=1.01-1.11, p<0.01). Multiple regression analyses revealed that dementia severity was associated with an interaction between the TE2/(TE1+TE2) ratio and serum folate (B=4.59 (SE=1.48), beta=1.22, 95% C.I.=1.62-7.56, p<0.005). None of the other potential mediators of this association (body mass index, sex hormone binding globulin, homocysteine levels, ApoE genotype, smoking, diabetes, blood pressure) was significant.

MAIN FINDINGS: A high ratio of estradiol to total estrogens is associated with AD but, in subjects with a high ratio, the dementia severity was lower in those with high serum folate levels.

CONCLUSIONS: If this association is causal, then supplementation with folic acid might be considered in future studies on ERT in AD....

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Journal Article 2002; 23(2): 149-154 PubMed PMID: 12011801 Citation  Keywords:  Animals, Cells, Cultured, Enzyme Inhibitors:pharmacology, Female, Follicle Stimulating Hormone:blood, Leptin:pharmacology, Luteinizing Hormone:blood, Neuropeptide Y:pharmacology, Nitric Oxide:metabolism, Pituitary Gland:cytology, Rats, Rats, Inbred WKY, o.   

OBJECTIVES: The aim of this study was to investigate the influence of NMMA on the mechanism of leptin and NPY action in in vivo and in vitro on pituitary hormone release by female rats in diestrus.

METHODS: In vivo experiments based on four-day ip injections of: 1) murine recombinant leptin (mrLep); 2) human NPY; 3) saline; 4) NMMA (50 microg) was applied prior to administration of mrLep; 5) NMMA (50 microg) was applied prior to administration of NPY; 6) NMMA (50 microg); 7) NMMA (350 microg) was applied prior to administration of mrLep; 8) NMMA (350 microg). The blood samples for LH and FSH were collected after decapitation of animals on the fifth day of study. In vitro experiments studied the effects of these peptides on LH release from pituitary cell culture.

RESULTS: In vivo: Leptin+ NMMA (50 microg) stimulated LH. NPY+ NMMA (50 microg) increased LH. NMMA (350 microg) stimulated FSH release. In vitro: The stimulatory effect of leptin on LH release in vitro was observed after 120 min of incubation, but after 60 mins of incubation the inhibitory effect of leptin on LH release was increased by NMMA. Leptin +NMMA (vs NMMA) decreased LH release with highest statistical significance. NPY 10 nM 60 min after incubation decreased LH release. There was no effect of NMMA on LH release.

CONCLUSION: In vivo results show, that NO probably mediates in leptin action on LH release. Moreover, effects of leptin on LH release from cultured pituitary cells are dependent on time of incubation. NPY decreased LH release in vitro....

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Journal Article 2002; 23(2): 141-148 PubMed PMID: 12011800 Citation  Keywords:  Adrenergic alpha-Agonists:pharmacology, Adrenergic beta-Agonists:pharmacology, Animals, Cells, Cultured, Drug Synergism, Female, Fenoterol:pharmacology, Granulosa Cells:cytology, Neuropeptides:pharmacology, Phenylephrine:pharmacology, Pituitary Adenylate .   

OBJECTIVE: VIP and PACAP, two structurally related peptides, stimulate c AMP, steroidogenesis and progesterone (PROG) release from cultured rat granulosa cells. VIP and PACAP(38) are known to mimic the effects of beta-adrenergic receptor stimulation in the rat pinealocytes causing an increased melatonin synthesis. These effects were markedly potentiated by alpha(1) adrenergic receptor stimulation.

METHODS: We examined the influence of phenylonephrine (PHEN) (10(-4) M and 10(-5) M)-alpha(1) adrenergic receptor agonist and fenoterol (FEN) (10(-5) M)-beta(2) adrenergic receptor agonist on PROG accumulation stimulated by VIP (10(-6) M) and PACAP (10(-7) M) in cultured ovarian granulosa cells of cyclic rats (diestrus) after 2 h and 24 h incubation. The PROG concentrations in supernatants were measured with RIA tests.

RESULTS: VIP, PACAP(38), PHEN and FEN stimulated PROG accumulation after 2 h incubation. The PROG accumulation stimulated both by FEN and VIP, and by FEN and PACAP(38) was not additive. PROG accumulation stimulated by VIP and PACAP(38) was strongly potentiated by PHEN-alpha(1) adrenergic agonist.

CONCLUSION: The alpha(1) adrenergic potentiation of VIP and PACAP(38) stimulatory effects on PROG release from granulosa cells culture was found. VIP, PACAP(38) and beta(2) adrenergic receptors activation may share the same postreceptor mechanism. There exists simultaneous activation of different receptors -- peptidergic and adrenergic ones in cultured granulosa cells of adult cyclic rat....

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