Biomedical subjects

Michal Karasek

Publications and source records attributed to Michal Karasek.

18 recordsLinked to original sources

PubMed2003

Melatonin inhibits growth of diethylstilbestrol-induced prolactin-secreting pituitary tumor in vitro: possible involvement of nuclear RZR/ROR receptors.

Melatonin exerts a marked antiproliferative action in numerous experimentally-induced tumors in vivo as well as in both animal and human cell lines in vitro. However, the mechanisms of oncostatic action of melatonin is not clear, and the involvement of both membrane and nuclear receptors are suggested. Therefore, the aim of this study was to investigate effects of melatonin, and both agonist (CGP 52608), and antagonist (CGP 55644) of RZR/ROR nuclear receptors on the growth of diethylstilbestrol-induced rat prolactin-secreting pituitary tumor cells in vitro. Pituitary tumors were induced by subcutaneous implantation of a single silastic capsule containing 10 mg of diethylstilbestrol in 4-wk-old male Fischer 344 rats. Four months after the implantation of capsules the animals were killed by decapitation, pituitary tumors were aseptically removed, mechanically dispersed, and enzymatically digested with 0.2% collagenase and 0.2% hyaluronidase. The cells (6 x 105 cells/well) were incubated for 24 hr in the presence of melatonin, CGP 52608, CGP 55644 and CGP 55644 plus melatonin (at the concentrations of 107 and 10-9 m) at 37 degrees C in the humidified atmosphere of 95% air and 5% CO2. The group with the addition of solvent only served as control. The growth of cell was measured using the EZ4U system. Statistical analysis was performed using ANOVA followed by LSD test. Both melatonin and CGP 52608 significantly suppressed growth of tumor cells in vitro in both used concentrations. CGP 55644 stimulated growth of tumor cells and blocked the inhibitory effects of melatonin in vitro. Results of the present study as well as other experimental evidence strongly support the hypothesis that both membrane and nuclear receptors are involved in the oncostatic action of melatonin, and indicate that nuclear signalling plays an important role in this process.

Animals↗

PubMed2002

Melatonin and aging.

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.

Aging↗

PubMed2002

Effects of six months melatonin treatment on sleep quality and serum concentrations of estradiol, cortisol, dehydroepiandrosterone sulfate, and somatomedin C in elderly women.

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.

Aged↗

PubMed2002

Oncostatic action of melatonin: facts and question marks.

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.

Animals↗

PubMed2002

Melatonin in clinical oncology.

The aim of this article is provide a survey of the current knowledge relating to the analysis of melatonin and its administration to cancer patients. On the basis of this compilation of data it can be discussed under which conditions melatonin may be used for diagnostic and/or therapeutic purposes in clinical oncology. Melatonin is depressed in patients with cancers of different origins during the phase of primary tumour growth whereas a normal or sometimes elevated pineal melatonin secretory activity is found during early stages of tumour development or when recidivations arise. The clinical studies of Lissoni show that melatonin, particularly if combined with interleukin-2, is able to favourably influence the course of advanced malignant disease leading to a prolonged survival as well as to an improved quality of life. These findings require to be verified by independent and controlled replication studies. If they can be confirmed it should be attempted to administer melatonin to patients with earlier stages of cancer parallel to standard oncological treatment regimens. In such trials it should be tested whether a substitutional therapy in patients with endogenously depressed melatonin may favourably affect the course of the disease both in quantitative (inhibitory effect on tumour growth and spread) and qualitative terms (improved performance status).

Antineoplastic Agents↗

PubMed2002

Effects of melatonin and melatonin receptors ligand N-[(4-methoxy-1H-indol-2-yl)methyl]propanamide on murine Colon 38 cancer growth in vitro and in vivo.

OBJECTIVES: Our previous study suggest that oncostatic action of melatonin (MLT) depends mainly on nuclear RZR/ROR receptors. However, we cannot exclude the involvement of membrane receptors in the control of tumor growth. In the present study the effects of MLT and N-[(4-methoxy-1H-indol-2-yl)methyl]propanamide (UCM 386 - antagonist of membrane MT(1) receptor and partial agonist of membrane MT(2) receptor) on murine transplantable Colon 38 cancer were investigated in vitro and in vivo conditions. MATERIAL AND METHODS: The experiments were performed on adult male B6D2F1 mice strain. In vitro the cell proliferation was measured using modified Mosmann method. In the experiment performed in vivo, we assessed the cell proliferation, apoptosis and proliferation/apoptosis ratio (P/A). The incorporation of bromodeoxyuridine into tumor cell nuclei was used as an index of cell proliferation (labeling index-LI). The labeling of apoptotic cells according to TUNEL method was considered as an index of apoptosis (AI). RESULTS: In vitro MLT and UCM 386 decreased the cell proliferation, but administration of MLT and UCM 386 together did not change the inhibitory effect of MLT alone. In vivo MLT and UCM 386 alone decreased LI and the addition of UCM 386 to MLT did not diminish the antiproliferative effect of MLT. Melatonin and UCM 386 injected alone also increased the AI. Moreover, both compounds given together exerted the additive effect on tumor apoptosis. MLT and UCM 386 alone or together also significantly decreased P/A ratio which is additional parameter confirming the inhibition of tumor growth. CONCLUSION: The obtained data together with our earlier observations suggest that oncostatic effect of MLT depends on acting via both MT(2) and RZR/ROR nuclear receptors

Animals↗

PubMed2002

Expression of melatonin MT(1) and MT(2) receptors, and ROR alpha(1) receptor in transplantable murine Colon 38 cancer.

OBJECTIVES: There are some data suggesting that melatonin exerts oncostatic action through membrane as well as nuclear receptors. In previous studies we demonstrated the antiproliferative and proapoptotic action of melatonin on transplantable murine Colon 38 adenocarcinoma cells. Therefore, the aim of the present study was to determine whether the membrane melatonin receptors MT(1) and MT(2) as well as the nuclear receptor RZR/ROR alpha are expressed in Colon 38 cells. MATERIAL AND METHODS: Adult male B6D2F1 mice were used in this experiment. The induction of tumor was conducted by subcutaneous injection of 0.2 mL of a 33% suspension of Colon 38 cancer cells into axillary region. Expression of mRNA encoding MT(1) and MT(2) melatonin membrane receptors was studied by RT-PCR analysis, and expression of ROR alpha(1) nuclear receptor protein was studied by Western blot analysis. RESULTS: The expression of mRNA encoding both MT(1) and MT(2) melatonin receptors was demonstrated in Colon 38 cancer cells. Moreover, immunodetection revealed the expression of MT(1) and ROR alpha(1) proteins in these cells. CONCLUSIONS: Our studies on Colon 38 adenocarcinoma cells support the concept that both membrane and nuclear receptors are involved in the oncostatic action of melatonin.

Animals↗

PubMed2002

Melatonin and magnetic fields.

There is public health concern raised by epidemiological studies indicating that extremely low frequency electric and magnetic fields generated by electric power distribution systems in the environment may be hazardous. Possible carcinogenic effects of magnetic field in combination with suggested oncostatic action of melatonin lead to the hypothesis that the primary effects of electric and magnetic fields exposure is a reduction of melatonin synthesis which, in turn, may promote cancer growth. In this review the data on the influence of magnetic fields on melatonin synthesis, both in the animals and humans, are briefly presented and discussed.

Animals↗

PubMed2002

Circadian serum melatonin profiles in patients suffering from chronic renal failure.

OBJECTIVES: In spite of broad interest, intensive studies on function of melatonin have not yielded much information about relationships between this hormone and kidneys in health, and particularity, in disease. Very little is known about the circadian plasma melatonin concentrations in patients with chronic renal failure (CRF). There are only a few studies dealing with melatonin concentrations in renal diseases, mainly performed in hemodialyzed patients with end-stage renal disease (ESRD). Moreover, the most melatonin assays were performed during the daytime, and the results are conflicting. Therefore, the aim of the present study was to determine the circadian melatonin profiles in patients with different stages of CRF. MATERIAL AND METHODS: Twenty four patients (13 males and 11 females) with CRF aged 35 to 58 years (mean+/-SEM: 47.0+/-1.6 years) were included in the study. Patients were divided into two groups: group 1 -- patients with compensated CRF (serum creatinine: 2.0-5.0 mg/dL), group 2 -- patients with ESRD (serum creatinine: > 8,0 mg/dL). The control group consisted of 20 healthy volunteers (10 males and 10 females) aged 35 to 55 years (mean+/-SEM: 46.0+/-1.5 years) checked not to have renal failure [serum creatinine: 0.8-1.4 mg/dL], and matched according to sex and age. Blood samples were collected at 08:00, 12:00, 16:00, 20:00, 24:00, 02:00, 04:00, and 08:00 h. Melatonin concentration was measured by enzyme immunoassay. RESULTS: In both groups of patients with chronic renal failure, i.e. in patients with compensated disease and in patients with end-stage renal disease melatonin nocturnal concentrations were significantly lower then those in healthy volunteers. Moreover, in patients with compensated renal failure also day-time melatonin concentrations were significantly depressed. Area under curve was significantly lower in both groups of patients in comparison with the control group. CONCLUSIONS: The mechanism of depressed melatonin concentrations in CRF observed in our study remains unclear. However, it seems possible that decline in melatonin levels is due to impairment in adrenergic function that occurs in CRF. Because the studies on the melatonin secretion in CRF bring about conflicting results, the relationship between renal diseases and melatonin secretion needs further investigations.

Adult↗

PubMed2002

Future of melatonin as a therapeutic agent.

Report of the round table conference summarizing the International Symposium on "Melatonin: Clinical Significance and Therapeutic Applications" is presented in this article. Some sleep disorders and circadian rhythm disturbances are the widely accepted indications for melatonin treatment. However, other possibilities for use of melatonin in the therapy should be also taken into account, including a co-treatment in cancer patients and free radical-related diseases. All aspects of the possible therapeutic use of melatonin as well as its safety, dosage, side effects and contraindications are discussed herein based on the round table conference and they are presented in this paper.

Animals↗

PubMed2000

Melatonin concentrations in patients with large goiter before and after surgery.

OBJECTIVES: Surgical removal of a very large goiter may traumatize adjacent anatomical structures. The manipulations that involve superior cervical ganglia may alter melatonin secretion. To test this hypothesis we decided to study diurnal serum melatonin profiles in patients with a very large goiter before and after the surgery. MATERIAL AND METHODS:The study was performed on 10 women (mean age-46.5+/-1.6 years; mean+/-SEM; range 39-54 years) with very large non-toxic nodular goiter (mean thyroid volume-125.8+/-25.9 cm (3); mean+/-SEM; range 82.6-326.7 cm(3)). Diurnal serum melatonin profiles were estimated two days before the operation and 10 days after the surgery. Blood samples were collected at 08:00, 12:00, 16:00, 20:00, 22:00, 24:00, 02:00, 04:00, 06:00 and 08:00 h. Melatonin concentration was measured using RIA kit. RESULTS: Nocturnal serum melatonin concentrations (at 24, 02, and 04 hours) were significantly higher after the surgery than before the operation. CONCLUSIONS: Very large goiter may compress the superior cervical ganglia altering indirectly the melatonin synthesis. It cannot be excluded, however, that the presence of the large goiter in some other way affects melatonin secretion.

Journal Article↗

PubMed2000

Testosterone levels and bone mineral density in young healthy men and in young infertile patients.

OBJECTIVES. Although relatively little information exists concerning bone mineral density (BMD) in men, it has been demonstrated that similarly to observations in women, BMD decreases also with age in men, although to a smaller extent, and osteoporosis is increasingly recognized. Most reports concentrate, however, on men of advanced age. Therefore, we decided to investigate BMD in young healthy volunteers and in young patients suffering from infertility, and to compare it with serum tes-tosterone levels. MATERIAL AND METHODS. The study was performed on 80 men divided into two groups. The first group consisted of 39 young healthy men (mean age 22.1+/-0.3 years; range 20-29). The second group consisted of 41 infertile men with oligozoospermia (mean age 28.0+/-0.5 years; range 23-34). Serum testosterone levels and BMD were measured in each subject. RESULTS. Decrease in BMD (T-score below -0.3) was observed in 35.9% of the subjects in the group of young healthy men and in 60.9% of the subjects in the group of infertile patients. Among these numbers -penia (T-score between -1 and -2.5) was found in 4 subjects (10.3%) in the group of young healthy men and in 13 subjects (31.7%) in the group of infertile patients. There was a positive correlation between testosterone concentrations and BMD as well as T-score both in healthy subjects and in infertile patients. CONCLUSION. Results of the present study indicate that attention should be paid to testosterone deficiency in the young age in terms of the potential risk of decreased bone mineral density in the advanced age.

Journal Article↗

PubMed2000

Serum melatonin circadian profile in women suffering from the genital tract cancers.

OBJECTIVES: Although there is increasing evidence that the pineal gland may play a role in human malignancy, the studies on melatonin concentrations in different types of malignant tumors brought about controversial results. However, changes in melatonin concentrations have been observed in some types of human malignant tumors. Therefore we decided to study the circadian melatonin rhythm in patients suffering from malignant tumors of the female genital tract, and to compare them with subjects free from neoplastic disease (healthy volunteers and patients with myomatous uterus). MATERIAL AND METHODS: A total of 46 women were analyzed in this study. The subjects were divided into 3 groups. The first group consisted of 23 patients with malignant tumors of the genital tract (mean age 50.3+/-2.2 years; mean+/-SEM, range 32-77 years). The second group consisted of 16 healthy volunteers (mean age 50.9+/-1.8 years; mean+/-SEM, range 42-63) who served as the first control group, whereas the third group consisted of 7 subjects who suffered from myomatous uterus (mean age 45.7+/-2.3 years; mean+/-SEM, range 39-56) and served as the second control group without malignancy. Blood samples were collected at 08:00, 12:00, 16:00, 20:00, 22:00, 24:00, 02:00, 04:00, 06:00 and 08:00 h. Melatonin concentration was measured using RIA kit. RESULTS: There were no significant differences in circadian melatonin profiles among the three groups studied. Taking into consideration the type of tumor of the genital tract, significantly lower melatonin secretion has been found in patients with endometrial cancer in comparison with tumor-free control groups, whereas no significant differences in melatonin secretion have been observed between tumor-free control groups and patients with invasive ovarian cancer and squamous cervical cancer. However, significant differences have been observed between endometrial cancer and invasive ovarian cancer. CONCLUSION: Its seems probable that melatonin concentrations in human malignancy may, at least partly, depend on hormone dependency of the particular type of tumor.

Journal Article↗

PubMed2000

Comparative quantitative ultrastructural study of pinealocytes in eight mammalian species.

OBJECTIVES: The studies related to quantitative ultrastructural features of mammalian pinealocytes, especially in comparative aspects, are relatively rare. Quantitative ultrastructural studies in many mammalian species are lacking. Because of the existence of differences in diurnal melatonin profiles in various species it seemed interesting to compare the ultrastructure of pinealocytes in various mammalian species, both laboratory and domestic animals. MATERIAL AND METHODS: The pineal glands of the following mammalian species have been examined: mouse, rat, Syrian hamster, gerbil, sheep, horse, pig and European bison. For each species 4 adult animals (2 males and 2 females) were used. Cross-sectional areas of the pinealocyte and its nucleus and the relative volumes of the following cytoplasmic organelles were analyzed: mitochondria, lysosomes, Golgi apparatus, granular endoplasmic reticulum, and lipid droplets. The relative volumes of membrane-bound bodies (MBB) in the pig pinealocytes, pigment granules in the horse pinealocytes, and calcareous concretions in the gerbil pineal gland were also analyzed. In addition, numerical density of dense-core vesicles and "synaptic" ribbons was estimated. RESULTS: Ultrastructure of pinealocytes in examined species shows many common features, and existing differences are of quantitative nature only. The observed qualitative differences include MBB in the pig, abundance of pigment granules in the horse, and calcareous concretions in the gerbil. Relative volumes or the numbers of some cell structures (mitochondria, Golgi apparatus, lipid droplets, dense-core vesicles and "synaptic" ribbons) show distinct interspecie differences, whereas those of other cell structures (granular endoplasmic reticulum, lysosomes) are similar in all studied species. CONCLUSIONS: The ultrastructural features of pinealocytes in all examined species confirm earlier suggestions of high activity of these cells. No distinct correlation has been found between the type of melatonin secretion and ultrastructural patterns of pinealocytes. It should be stressed, however, that the ultrastructure of pinealocytes in the present study was studied during the daytime, whereas differences in melatonin secretion are observed at night.

Journal Article↗

PubMed1999

Pineal gland, melatonin and cancer. NEL Review.

Studies on the relationship between the pineal gland, melatonin and neoplastic disease have recently become one of the most fascinating aspects of pineal research. The first data suggesting a link between the pineal and cancer were published 70 years ago. However, the real progress in this area of research has been made in the last two decades. The bulk of the experimental evidence indicates the influence of the pineal gland on the malignant tumor formation and/or growth. The majority of reports point toward the oncostatic action of the pineal, exerted most probably by its hormone, melatonin, via different mechanisms, including modulation of endocrine and immune systems and direct antiproliferative action. The mechanisms of the oncostatic action of the pineal seem to be, however, very complex. There is some indication that the pineal gland may also play a role in human malignancy. Alterations in melatonin concentrations have been demonstrated in various tumor types including breast cancer, prostate cancer, colorectal carcinoma, and uterine cancer. Moreover, melatonin has been reported to be helpful in therapy of advanced cancer of various types. However, detailed 24h melatonin profiles must be studied in large numbers of patients with different types of tumors before determining whether melatonin concentrations have any diagnostic and/or prognostic values in cancer patients. Moreover, well designed clinical trials should be performed on the possible therapeutic significance of melatonin in neoplastic disease.

Journal Article↗

PubMed1999

Guest Editorial.

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Journal Article↗

PubMed1999

Melatonin in humans-where we are 40 years after its discovery.

Although the pineal gland was well known for more than 2000 years and has been documented since Galen (130-200 AD), for many centuries different theories concerning its function were presented. The organ was believed to be a sphincter (ancient Greeks), the point at which the soul preeminently controls the body (Descartes, 1596-1650), a rudimentary organ (up to the 19th century), and a gland having endocrine function. Endocrine function of the pineal was postulated already at the end of 19th century and the beginning of the 20th century with the notion of antigonadotropic pineal influence, and the functional cooperation between the pineal and hypothalamo-hypophysial axis, but no secretory substance responsible for the gland function was known. In 1958 Lerner and coworkers succeeded in isolating from bovine pineal glands the compound termed melatonin because of its blanching effect on melanophores. This discovery constituted the milestone for further pineal research. Since then the knowledge of the structure and function of the pineal gland has tremendously increased, especially during the last two decades. However, it should be stressed that many problems in pineal research still must be solved. In this paper, the recent knowledge on the role of melatonin in humans is briefly presented.

Journal Article↗

PubMedDate not supplied

Effect of superior cervical ganglionectomy on the ultrastructure of pinealocytes in the Djungarian hamster (Phodopus sungorus): quantitative study.

OBJECTIVES: Superior cervical ganglia are of crucial importance in regulating the secretion of the pineal hormone melatonin. Changes in pineal morphology have been observed in many mammalian species after sympathectomy. Therefore, we decided to investigate the ultrastructure of Djungarian hamster pinealocytes following superior cervical ganglionectomy. MATERIAL AND METHODS: Eight adult female Djungarian hamsters (Phodopus sungorus) were used in this study. The superior cervical ganglia were removed bilaterally in four animals, whereas the other four animals served as sham-operated controls. The pineal glands were removed four weeks after the operation and processed for electron microscopic study. The cross-sectional areas of pinealocyte and its nucleus, and relative volume of mitochondria, Golgi apparatus, lysosomes, granular endoplasmic reticulum, and glycogen particles as well as the numbers of dense-core vesicles and "synaptic" ribbons were estimated using a digital analyzer connected on-line to IBM-PC computer. Statistical analysis of the data was performed using Student's t test and Snedecor F test. RESULTS: Significant reduction in the cross-sectional areas of the pinealocyte and its nucleus as well as in the relative volumes of mitochondria and glycogen particles was observed after superior cervical ganglionectomy in comparison with sham-operated controls. Sympathectomy resulted also in reduction of the number of dense-core vesicles. On the contrary 2,5 fold increase in the number of "synaptic" ribbons was observed in ganglionectomized animals in comparison to sham-operated controls. CONCLUSION: Deprivation of sympathetic innervation leads in Djungarian hamsters not only to suppression of melatonin synthesis and secretions but, as appears from our studies, induces also morphological changes suggesting lower metabolic and secretory activity of pinealocytes.

Animals↗