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Journal Article 2001; 22(6): 449-452 PubMed PMID: 11781543 Citation  Keywords:  Animals, Body Weight, Circadian Rhythm:physiology, Leptin:blood, Male, Melatonin:metabolism, Pineal Gland:metabolism, Rats, Rats, Wistar,.   

OBJECTIVES: Exogenous and endogenous melatonin decrease leptin release. It is not known whether melatonin also has an effect on circadian release pattern of leptin. So, this study was planned to investigate the possible changes in the circadian release of leptin following pinealectomy.

METHODS: A group of rats were surgically pinealectomized while some others were exposed to sham operation. The animals were decapitated at 13.30 p.m. and 01.30 a.m. Serum leptin levels were measured by radioimmunoassay.

RESULTS: Serum leptin levels at 13.30 p.m. were lower than the values at 01.30 a.m. in both pinealectomized (P<0.002) and sham rats P<0.001). Serum leptin levels measured at 13.30 p.m. and 01.30 a.m. were significantly elevated (P<0.05 and P<0.01, respectively) in the pinealectomized rats in comparison to sham animals.

CONCLUSION: The circadian release of leptin does not seem to be regulated by melatonin release from the pineal gland whereas melatonin, physiologically released, may have a decreasing effect on leptin release....

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Journal Article 2001; 22(6): 441-447 PubMed PMID: 11781542 Citation  Keywords:  Age Factors, Animals, Antioxidants:pharmacology, Female, Gene Expression Regulation, Neoplastic:drug effects, Mammary Neoplasms, Experimental:drug therapy, Melatonin:pharmacology, Mice, Mice, Transgenic, Photoperiod, RNA, Messenger:analysis, Receptor, Erb.   

OBJECTIVES AND DESIGN: The effect and the mechanism of light regimen and melatonin on the development of mammary tumors in HER2/neu transgenic mice were investigated. Female HER-2/neu mice starting from the age of 2 months were kept under standard light/dark regimen (LD) or constant light illumination (LL) and a part of each group was given melatonin (20 mg/l) during the night time.

RESULTS: The exposure to LL failed to change the incidence of spontaneous mammary adenocarcinoma development, the size of mammary tumors, as well as the incidence and size of lung metastases. However, the number of tumors per mouse was significantly increased in the LL group as compared to the LD group. The number of mice bearing 4 and more tumors was higher in the LL group than in the LD group, whereas the number of mice bearing 1 to 3 tumors was lower in the LL group in comparison with the LD group. Melatonin decreased the incidence and size of mammary adenocarcinomas, and the incidence of lung metastases in the LD group but not in the LL group. The mean number of tumors per mouse was not changed by melatonin treatment in both light regimens. The number of mice bearing 4 and more tumors was reduced by melatonin more significantly in the LL group than in LD group. Melatonin treatment resulted in a 2.5-fold reduction in the expression of HER-2/neu mRNA in mammary tumors from HER-2 /neu transgenic mice.

CONCLUSION: The data demonstrate the influence of the LD light regiment and melatonin treatment in the development of spontaneous mammary tumors in HER-2/neu mice suggesting a melatonin-dependent modulation of HER-2/neu gene expression in mammary adenocarcinoma....

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Journal Article 2001; 22(6): 435-440 PubMed PMID: 11781541 Citation  Keywords:  Animals, Gene Expression:physiology, Gonadotropin-Releasing Hormone:metabolism, Luteinizing Hormone:genetics, Pituitary Gland, Anterior:physiology,.   

: Detailed studies have been focused on the mechanisms by which the rat alpha and LHbeta genes are differentially regulated by GnRH and indicate that differential sensitivity to the second messenger exists in a physiological context. Differential signaling from the GnRH receptor may be a mechanism for preferential regulation of luteinizing hormone subunit gene transcription; however which of these genes are specifically regulated by PKC or calcium and how GnRH pulsatility could preferentially activate individual pathways of second messengers within gonadotrope cells remain unclear. Several transcription factors that have profound effects on basal and/or GnRH-stimulated LHbeta gene promoter activity have been identified: SF-1, Egr-1, Sp-1. A model explaining possible interactions among them in mediating GnRH responsiveness of the LHbeta gene has been proposed: Sp1, SF-1 and Egr-1 form a tripartite GnRH response element which is sensitive to the spacing changes between the upstream Sp1 binding sites and the downstream SF-1/Egr-1 binding elements and SF-1 plays a critical role in integrating the effects of Sp1 and Egr-1. GnRH responsive element located on LHbeta gene promoter in position between -495 to -342 has been identified. At 3'-end of the promoter three Sp-1 binding sites have been identified: position -416, sequence: GGGGGCTGGG and two sites almost completely overlapping, position -403, sequence; GGGGCGGCGCCCA while at the 5'region of the promoter one Sp-1 binding site exists: position -450, sequence: ACCACACCCATTTTTGG. The 5'Sp1 site overlaps a CArG box (at -443 to -434, sequence: CCATTTTTGG) which seems to be essential in LHbeta gene sensitivity for pulsatile GnRH stimulation....

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Journal Article 2001; 22(6): 432-434 PubMed PMID: 11781540 Citation  Keywords:  Animals, Antioxidants:pharmacology, Carcinoma, Ehrlich Tumor:drug therapy, Cattle, Cell Extracts:pharmacology, Male, Melatonin:pharmacology, Mice, Mice, Inbred AKR, Neoplasm Transplantation, Pineal Gland:physiology, Survival Rate,.   

UNLABELLED: OBJECTIVES Pineal gland may have a role in organism's protection against cancer. Melatonin as well as still unidentified low-weight molecular pineal substance(s) have been reported to have growth inhibitory effect on different tumor cells. We tested the influence of melatonin and of a bovine pineal extract on the survival rate of AKR mice inoculated with Ehrlich ascites. The tumor is known to have an accelerated development after pinealectomy.

MATERIAL AND METHODS: Male AKR mice, kept under a 14/10 hours - Light /Dark cycle, were inoculated intraperitoneally (i.p.) with 1.5x 10(6) Ehrlich ascites cells. On day three after inoculation the animals were divided in three groups (n=10). Each animal received i.p. daily (20.00H), until their death, 250 microl of solution containing melatonin (250 microg), pineal extract (equivalent of 1 bovine pineal gland) or saline.

RESULTS: The average survival rate of the animals treated with melatonin was shorter (14.8+/-2.23 days) compared to control animals (21.9+/-2.21 days)(p=0.01). The animals treated with the pineal extract had a longer survival rate (22.6 +/- 1.8 days) but not statistically significant. The pineal extract was not available for testing at higher doses.

CONCLUSION: In our model, melatonin had a deleterious effect on the survival rate raising the question whether it is correct to assume that the hormone shows lack of adverse reactions....

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Journal Article 2001; 22(6): 427-431 PubMed PMID: 11781539 Citation  Keywords:  Animals, Female, Gonadotropin-Releasing Hormone:metabolism, Hypothalamus:metabolism, Leptin:pharmacology, Luteinizing Hormone:blood, Pituitary Gland:metabolism, Rats, Sexual Maturation:drug effects,.   

OBJECTIVES: The aim of the present paper was to determine the sensitivity of the GnRH-LH axis to leptin administration during sexual maturation in female rats.

METHODS: For this purpose the hypothalamic concentration of GnRH, the pituitary content and the plasmatic levels of LH were determined in prepubertal (15 days of age) and peripubertal female rats (30 days of age), treated with leptin at a dose of 30 microg/kg. i.p. in a single injection, 90 min before sacrifice.

RESULTS: The results indicate that leptin significantly increased the GnRH concentration at 15 days of age (p <0.01). At 30 days of age the hormone did not significantly modify the hypothalamic GnRH content. Leptin increased the pituitary LH levels, both in prepubertal and peripubertal rats. Nevertheless, while the increase at 15 days of age was around 180%, in peripubertal rats it was about 51,2 %. In spite that leptin significantly increased LH plasmatic levels at both ages (p < 0.01 ), in rats of 15 days of age leptin increased LH in about 244%, at 30 days of age this increase was only about 102%.

CONCLUSION: These results clearly demonstrated that leptin has stimulatory effect on gonadotrophin axis been higher in prepubertal than in peripubertal rats. On these basis, and on the results of previous papers, (in which it has been demonstrated that the hypothalamic control of gonadotrophins by neurotransmitters and neuromodulators also showed qualitative and quantitative changes during sexual maturation), it is proposed that these differences are connected with the maturation of the neuroendocrine mechanisms involved in the regulatory action of leptin on the gonadotrophins axis....

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Journal Article 2001; 22(6): 417-426 PubMed PMID: 11781538 Citation  Keywords:  Aflatoxin B1:toxicity, Animals, Antioxidants:pharmacology, Apoptosis:drug effects, Caspase 3, Caspases:metabolism, Glutathione:metabolism, Glutathione Peroxidase:metabolism, Glutathione Reductase:metabolism, Glutathione Transferase:metabolism, Lipid Perox.   

OBJECTIVES: A study of liver apoptosis after aflatoxin B1 (AFB1) administration and the effect of melatonin (MEL) was investigated in male rats.

METHODS: Five groups of 15 rats each were used: controls, MEL Soln-treated rats (MEL dose,5 mg/Kg body wt), AFB1-treated rats (50 microg/Kg body wt), MEL Soln+AFB1-treated rats, and MEL micro-capsules (MEL-MC)+ AFB1-treated rats. After 8 weeks of treatment, biochemical measurements in liver homogenates and histopathological examination of liver sections of different groups using light and transmission electron microscope were done. The caspase-3 enzyme activity, apoptotic marker, was determined in liver tissues. Because hepatic antioxidants represent the major defence against toxic liver injury, and they act as anti-apoptosis. So, the levels of glutathione (GSH) and zinc (Zn) and the enzyme activities of glutathione reductase (GR), glutathione peroxidase (GSPx) and glutathione-S-transferase (GST) were determined. In addition, the levels of malondialdehyde (MDA), a lipid peroxidation product, and nitric oxide (NO) levels were measured.

RESULTS: The levels of caspase-3 activities in AFB1 group were significantly higher than control group. The apoptosis was associated with degenerative and necrotic changes in the hepatocytes. Concomitantly, the levels of MDA and NO in liver tissues were significantly increased while the levels of GSH, Zn and enzyme activities of GSPx and GR in liver tissues were significantly decreased in AFB1 group compared to their levels in controls. Caspase-3 activity was positively correlated with MDA while negatively correlated with GSH, GSPx and GR in rat livers treated with AFB1. The apoptotic rate was significantly reduced when MEL co-administrated with AFB1. In rats which received MEL with AFB1, the levels of MDA and NO in liver tissues were significantly reduced while GSH and Zn levels and GSPx, GR and GST activities were significantly increased compared to AFB1 group. When MEL-MC co-administrated with AFB1 appeared more effective in reduction of apoptotic rate as detected by decline of caspase-3 activities (inhibition 66.82%) and confirmed by histopathology.

CONCLUSION: AFB1 can lead to direct or indirect caspase-3 activation and consequently to apoptosis in rat liver. MEL treatment of rats could enhance hepatic antioxidant/detoxification system which consequently reduce the apoptotic rate and the necrobiotic changes in the liver. MEL-MC exhibited an efficient protective effect against AFB1. Thus, clinical application of MEL as therapy should be considered in cases of aflatoxicosis....

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Journal Article 2001; 22(6): 413-416 PubMed PMID: 11781537 Citation  Keywords:  Humans, Neoplasms:diagnosis, Thermodynamics,.   

: All the theories of carcinogenesis have properly described this event from methodologically different points of view (medical, biological, social, biochemical psychological etc.). The point is that one should understand the thermodynamical rules underlying each of these approaches. On this level of knowledge, quantum thermodynamics combines matter and energy, while technical quantization in a novel way differentiates precancerous states as the dissipathogenic ones from the neoplasms as the newly formed dissipative structures (systems). From the essential nature of the neoplasm one can derive some general rules of therapy which focus mainly on: 1 degrees prevention and therapy of the dissipathogenic states, 2 degrees strengthening of the regenerative and defensive mechanisms of the organism and, finally, 3 degrees removal of neoplastic changes as widely as necessary but also as sparingly as possible. For a long time, these rules have been observed in reverse order. That cannot improve the medical outcome, which has not changed for a few dozen years, i.e. recovery depending on the clinical level at the moment of the diagnosis....

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Journal Article 2001; 22(6): 403-409 PubMed PMID: 11781536 Citation  Keywords:  Brain:enzymology, Brain Chemistry:genetics, Female, Gender Identity, Gonadal Steroid Hormones:physiology, Humans, Male, Sexual Behavior:physiology,.   

: Alterations of sex hormone levels during pre- or perinatal sexual brain organization - responsible for long-term changes of gonadotropin secretion, sexual orientation, and gender role behavior - can be caused by: 1. Genetic effects, i.e. mutations or polymorphisms of a) 21-hydroxylase genes on chromosome 6, b) 3beta-hydroxysteroid dehydrogenase genes in chromosome 1 or c) X-chromosomal genes, and 2. Epigenetic effects, such as a) stressful situations - especially in combination with mutations - and b) endocrine disrupters, e.g. the pesticide DDT and its metabolites, which display estrogenic, antiandrogenic, and inhibitory effects on the enzyme 3beta-hydroxysteroid dehydrogenase leading to increased levels of dehydroepiandrosterone and its sulfate as precursors of endogenous androgens and estrogens. In connection with the introduction and extensive use of the pesticide DDT, the following findings were obtained in subjects born before as compared to those born during this period: 1. The prevalence of patients with polycystic ovaries (PCO), idiopatic oligospermia (IO), and transsexualism (TS) increased significantly (about 3-4 fold). 2. Partial 21-hydroxylase deficiencies were observed in most patients with PCO and TS and some patients with IO born before this period. 3. In contrast, most patients with PCO and TS and several patients with IO born during the period of massive use of DDT displayed clearly increased plasma levels of dehydroepiandrosterone sulfate (DHEA-S) and DHEA-S/cortisol ratios suggesting partial 3beta-hydroxsteroid dehydrogenase (3beta-HSD) deficiencies. Interestingly enough, geneticists could not find any mutations of 3beta-HSD genes in such subjects. However, o,p'-DDT and/or its metabolite o,p'-DDD are strong inhibitors of 3beta-HSD, indicating their possible co-responsibility for such life-long ontogenetic alterations. Finally, some data suggest that endocrine disrupters may also be able to affect the development of sexual orientation....

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