Search

Progesterone (P4) and its analogues regulate various reproductive processes, such as ovulation, implantation, pregnancy maintenance and delivery. In these processes, an important role is played by the immune cells recruited to the female reproductive organs and tissues, where they are exposed to the action of P4. Progestins regulate cellular processes, acting through nuclear steroid receptors (nSRs), membrane P4 receptors (mPRs), and through the sensors. It remains unclear, what type of receptors is used by P4 and its derivatives to exert their effect on the immune cells and how similar their effects are in different types of these cells. We have previously synthesized new progesterone derivatives, among which two selective mPRs ligands, not interacting with nSRs were identified. The objective of this study was to examine the effects of P4 and new selective mPRs ligands on the expression of pro- and anti-inflammatory cytokines in activated human peripheral blood mononuclear cells (PBMCs), THP-1 monocyte cells, and Jurkat T cells. It was demonstrated that the action of P4 and selective ligands was unidirectional, but in different types of the immune cells, their effects were different, and sometimes even opposite. In PBMCs, exposure to these steroids resulted in the increase of mRNA and secreted protein levels of IL-1β, TNFα, and IL-6 cytokines, as well as in the increase of INFγ mRNA level, decrease of IL-2 mRNA level, increase of TGFβ mRNA level, and decrease of IL-4 mRNA and IL-10 secreted protein levels. In monocytes, similarly to PBMCs, expression of IL-1β and TNFα mRNA was increased, but expression of IL-10 was also increased, and the TGFβ expression statistically significantly remained the same. In Jurkat T cells, expression of IL-2 and TNFα mRNA decreased, while expression of IL-10 increased, and expression of TGFβ did not change. Thus, progestins act on the immune cells through mPRs and have both pro- and anti-inflammatory effects, depending on the phenotypes of these cells. The data obtained are important for understanding the complexity of the immune system regulation by progestins, which depends on the type of the immune cells and individual characteristics of the immune system.

Aim. To study changes in the indices of prooxidant and antioxidant systems in plasma in men with atrophic gastritis and gastric cancer. Materials and methods. The study included 60 healthy men, 42 patients with atrophic gastritis and 50 men, nicardipine patients with gastric cancer stage II according to TNM. All patients underwent serological diagnosis of diffuse atrophic gastritis (definition of pepsinogens and gastrin-17) and Helicobacter pylori infection. The diagnosis of "atrophic gastritis" was verified by morphological examination of biopsy specimens obtained during fibroesophagogastroduodenoscopy. Diagnosis of gastric cancer was carried out in the Krasnoyarsk regional oncologic dispensary on the basis of a comprehensive instrumental and morphological examination. All patients spectrophotometric methods in plasma was determined the content of diene conjugates (DC), malonic dialdehyde (MDA), glutathione-S-transferase (GST), glutathione peroxidase (GPO), superoxide dismutase (SOD) and catalase. Results. The concentration of SOD, GST, GPO and catalase had no significant differences in patients with atrophic gastritis and gastric cancer and prevailed in comparison with healthy persons. Patients with cancer of the stomach content in the blood plasma DK 2.7 times and MDA at 35.2 times higher than healthy individuals, indicating severe oxidative stress in patients with cancer. In patients with atrophic gastritis was observed similar but less pronounced pattern. Conclusion. The results indicate the presence of oxidative stress in men with atrophic gastritis and gastric cancer.

Background : Infectious complications — the leading cause of mortality in patients with multiple myeloma (MM), their appearance is regarded as an adverse prognostic factor in the course of the disease. Objective : The aim of our study was to evaluate the clinical and immunological features of infectious complications in patients with G- immunochemical MM to find the most informative indicators in their forecasting. Methods : A randomized controlled trial was made. All patients were divided into 3 groups for comparison: Group 1 (n =47) — MM patients, G-immunochemical variant with infection, Group 2 (n =54) — MM patients, G-immunochemical option no infectious complications, and Group 3 (n =125) — healthy volunteers. Research material was deoxygenated blood taken on admission of a patient to the hematology department before the pathogenetic treatment. Identification of G-variant was carried by immunofixation and electrophoresis. The immune status was assessed by indirect immunofluorescence. The concentration of IgA, M, E and G, and the levels of IL 2, IL 4, IL 8, TNF α, IFN γ in serum was determined by enzyme immunoassay. The activity of neutrophil granulocytes (NG) was studied by chemiluminescent analysis of spontaneous and induced production of reactive oxygen species. Statistical analysis was performed using the software STATISTICA v. 8.0 (USA). Results : We analyzed data from 101 patients with MM and 125 healthy volunteers. The average age of MM patients was 60.53±6.78 years. The group of healthy volunteers was similar in sex and age to groups of patients with MM. In patients with MM in the presence of infectious complications the researchers detected combined secondary development of T and B cell immunodeficiency, changes in non-specific immunity depended on the stage of the disease, unidirectional irregularities in spontaneous and induced chemiluminescence activity NG in II stage disease and multidirectional irregularities in stage III (p =0.045). Prevalence of the content of proinflammatory cytokines on inflammatory (p

Experiments on rats revealed sex-related differences in bilirubin concentration in the bile and bile flow rate against the background of obstructive cholestasis. These differences disappeared after gonadectomy. There were no sex-related differences in the rate of bilirubin excretion with the bile after removal of cholestasis, which was attained through different mechanisms in males and females.

Immunohistochemical study revealed overexpression of prolactin receptors in central and peripheral cells of intrahepatic grafts from H27 rat hepatoma without changes in compartmentalization compared to hepatocytes of intact animals. Experiments with gonadectomized animals showed that the hormonal regulation of prolactin receptors in both types of tumor cells does not differ from that in normal liver cells (positive estrogen-dependent regulation and negative androgen-dependent regulation).

The aim of the work was to study the role of cellular and humoral immunity in progression of myeloma disease (MD). The study included 97 patients and 125 age and sex-matched healthy volunteers. The state of cell-mediated and humoral immunity was evaluated at admission, before the pathogenetic treatment, by indirect immunofluorescence technique using anti-CD3, CD4+, CD8+, CD16+, CD19+, HLA-DR+ monoclonal antibodies. Serum IgA, IgM, IgE, IgG were measured by immunoenzymatic assay. The results were analysed using Statistica 7.0 (StatSoft, USA) program. The quantitative values are expressed as the median (Me) and interquartile range (C25-C75). Qualitative variables are presented as absolute values and percentage. The critical statistical significance level was taken as 0.05. The patients with MD developed combined secondary T, B-cell immunodeficiency. The disbalance between CD4+ cells and cytotoxic lymphocytes as well as signs of B-lymphocyte deficit increased with the progress of the disease. The number of NK-cells decreased at all stages of the disease. A rise in the serum level of LgC at all stages compared with control is an identifying sign confirming diagnosis of G-variant of myeloma disease.

The presence of prolactin receptor and peculiarities of its isoform expression in bile duct cells (cholangiocytes) differentially isolated from rat liver under different conditions were investigated in the present study. Normal cholangiocytes express prolactin receptor at relatively low level comparable to those of some prolactin-dependent tissues. Long receptor isoform is predominant in cholangiocytes but not in hepatocytes. The prolactin receptor level increases significantly under obstructive cholestasis due to evaluation of long and appearance of short isoforms. In rat cholangiocytes, unlike other tissues, the main positive regulators of prolactin receptor expression are cholestasis-induced factors instead of sex hormone and prolactin levels. Long isoform is predominant and induced primarily by cholestasis-induced factors.

The effects of obstructive cholestasis and sex hormones on the total content of prolactin receptor mRNA and ratio of mRNAs of its short and long isoforms have been studied in rat hepatocytes. Obstructive cholestasis caused insignificant changes in total content of prolactin receptor mRNA, but the proportion of mRNA of the long isoform increased. Comparison of prolactin receptor mRNA levels in gonadectomized and intact animals revealed opposite effects of male and female sex hormones on total mRNA, but both groups of these hormones increased the proportion of prolactin receptor short form mRNA. Changes in ratio of mRNA of receptor isoforms found in rat hepatocytes under obstructive cholestasis did not depend on levels of sex hormones. Obstructive cholestasis and sex hormones are suggested to regulate the content of long and short prolactin receptor isoforms in hepatocytes independently.

This work is devoted to the study of the role of iron ions in the carcinogenic and mutagenic activity of chrysotile. For this aim natural chrysotile was treated with ferric chloride (III), washed, crushed and intratracheally introduced into Wistar rats. When administered to rats intact chrysotile induced mesotheliomas in 27,9 + 4,6% of cases, and chrysotile modified with ferric chloride - in 1,3 +/- 1,3%. Mutagenicity of the same samples was studied in the micronucleus test when administered intraperitoneally to mice Fl (CBA x S57Bl6). Polychromatic erythrocytes in the bone marrow were investigated 24 hours after intraperitoneal administration. The frequency of polychromatic erythrocytes with micronuclei was decreased from 7,4 +/- 0,18 by 1000 due to the action of chrysotile, from 2,8 +/- 0,42 for 1000 after the introduction of a modified sample. It is hypothesized that the ferric chloride modifies the surface of asbestos fibers that reduces the induction of free radicals which are the primary cause of and carcinogenic effects of chrysotile.

Disturbances of the erythrocyte antioxidant system presented by LPO intensifi cation were detected in patients with multiple myeloma. Plasma concentrations of MDA in these patients were close to normal due to effective work of the nonenzymatic antioxidant system. Activities of antioxidant enzymes in the plasma were reduced, while catalase activity was high, and ceruloplasmin content did not differ from the control, this indicating suppression of the enzymatic component of the antioxidant system. In erythrocytes, the level of reduced glutathione was low, especially at stage III of the disease. Changes in SOD and catalase activities were similar to those in the plasma, while activities of glutathione-dependent enzymes were comparable to those in normal human erythrocytes.

The mechanisms of participation of multidrug-resistance proteins (MRPs) in sex difference pattern of drug efficiency and side effects have been analyzed. MRPs structure, their tissue and cellular localization, substrate specificity, and functions have been considered. Regulation of expression and activity of MRPs by endogenous metabolites, signal compounds, including sex hormones, as well as by drug agents have been represented. The role of nuclear receptors in the regulation of MRPs expression has been demonstrated. The data on sex differences in hepatic and renal MRPs expression and expression of nuclear receptors, participating in their induction, have been shown. The participation of MRPs in the formation of sex differences of drug pharmacokinetics has been discussed. Sex differences in representation and functional activity of MRPs in such excretory organs as liver and kidney was concluded would play the essential role in sex dependence of pharmacokinetics and efficiency of drug action.

During intraperitoneal administration of dispersiveness-comparable chrysotile or asbestos cement fibers to rats (20 mg thrice), mesotheliomas were found in 45.1 and 7.7% of cases respectively. Asbestos cement dust induced tumors in 2.5% of cases, which is of biological importance. Cement or freeze asbestos destruction cement dust failed to cause tumors. The latter were not detected in a control group receiving physiological saline. Asbestos cement fibers and fascicles are covered by a cement matrix. Fiber amorphization gradually occurs. In lung tissue, there may be destruction of the cement coat of fascicles and release of native chrysotile fibers that are carcinogenic.

A possibility of inheritance of androgen and basic genetic programs at the level of unusual estrogen-binding protein (UEBP) by daughter hepatocytes was investigated. Liver regeneration after partial ( 2 3 ) hepatectomy or after selective poisoning of hepatocytes of the central zone of hepatic lobules with CCl4 in adult rats were used as models of total and zonal proliferation of hepatocytes, respectively. UEBP content and the pattern of its tissue expression in the course of liver regeneration were monitored by radioligand and immunocytochemical technique. In animals of all groups possessing the androgen program of UEBP expression (intact, castrated and/or hypophysectomized males, and ovariectomized females treated with androgen) UEBP content was shown to be similarly high before initiation and after completion of liver regeneration. Unlike in males, in androgenized females a transient 4-fold increase of UEBP concentration on day 4 after partial hepatectomy was observed. In animals with a basic genetic program at the level of this protein (ovariectomized females, neonatally castrated males) only trace amounts of UEBP were observed in intact as well as in regenerated liver. The data were confirmed by immunocytochemical technique. A gradient mode of distribution of UEBP-contained cells within hepatic lobules with the highest specific staining around central veins was found by immunocytochemical technique in males. Specific staining of centrolobular and periportal hepatocytes was 7- to 10-fold in intact, and 4- to 6-fold in castrated and/or hypophysectomized males. In intact females specific staining was distributed uniformly at extremely low levels similar to that in periportal hepatocytes of males. Androgen administration to ovariectomized females stimulated a significant and stable increase of UEBP content in two layers of hepatocytes surrounding the central vein. Profiles of specific staining of hepatocytes within the hepatic lobules similar to that in control animals were observed after the completion of liver regeneration of different groups of rats. The results obtained suggest all the hepatocytes to be targets for androgen programming, natural in males or experimental in females, while the extent of expression of this program depends on the position of a hepatocyte within the liver lobules and the sex of the animal.

Gender-related differences in bilirubin concentration in post-cholestatic bile, bile excretion from the liver, and bile flow velocity disappeared in hyperprolactinemia in the presence of obstructive cholestasis. Gender-related differences in the alternative routes of bilirubin excretion appeared.

We studied concentrations of cortisol, its precursors and active form in human blood and relation to the changes in concentration of central and peripheral hormonal regulators (total 36 parameters) in healthy male volunteers aged 18-72 y.o. The study demonstrated a significant decrease in blood concentrations of unutilazed cortisol precursors (pregnenolone and progesterone) with advanced age accompanied by maintenance of total and free cortisol concentrations. We found age-related decrease in ACTH level that is a known hypophysial stimulant of cortisol and cortisol precursor synthesis in adrenal glands. Cortisol and ACTH levels in study population had different correlation behavior in relation to central and peripheral regulators for hormonal axes.cortisol level remains stable with advanced age in males despite the decrease in steroidogenic activity and blood ACTH level. This may be due to the imbalance in the regulation of cortisol and ACTH production by central and peripheral regulators especially by hormones of reproductive and somatotrophic axes.

Wistar rats were fed propoxur in their diet at 0, 500, 3000, and 8000 ppm during throughout their life. The number of tumors was equal in the control and experimental groups. These were hemoblastoses and breast and uterine tumors. All tumors occurred spontaneously in the rats. A few experimental animals were found to have bladder epithelial hyperplasia that might be pretumorous; however, no bladder tumors were detected. It is concluded that the investigations revealed no carcinogenic activity of propoxur.

Blood concentrations of hormone-inactive and active sex-steroid metabolites and their precursors were measured, taking into account changes in protein-peptide hormones that control the reproductive axis (in a total of 14 parameters) in men in the 18- to 72-year-old age interval. A significant decrease in the blood concentration of unutilized precursors of active sex steroids (pregnenolone, progesterone, dehydroepiandrosterone, and its sulfate), unbound testosterone, androstenedione (an inactive metabolite of testosterone), and an active metabolite, 5alpha-dihydrotestosterone was determined after the age of 35. However, the level of total testosterone and of estradiol (another active metabolite of testosterone) remained constant. The systems regulating the production of active sex steroids resisted a higher load, causing the luteinizing and follicle-stimulating hypophyseal hormones and activin of steroidogenic glands to increase and correlate positively with age; these hormones correlated negatively with certain sex steroids that realize negative feedback. A decrease in the level of adrenocorticotropic hypophyseal hormone with age suggests a more substantial role for adrenal glands as compared to that of testicles in reducing the blood concentration of active sex steroids. In general, despite the reduced activity of steroidogenic glands in 60- to 70-year-old men, their testosterone and estradiol concentrations remain unchanged, due to coordinated growth in the concentration of luteinizing and follicle-stimulating hypophyseal hormones, and to the activin of steroidogenic glands, which stimulated sex steroid biosynthesis. At the same time, the androgen effect was inhibited as a result of reduced levels of unbound testosterone and 5alpha-dihydrotestosterone.

Regular intraperitoneal administration of peptone to rats was initiated immediately and 12 months after intraperitoneal thrice injection of crokidolite UICC in a dose of 20 mg. The rate of peritoneal mesotheliomas was 37.8% after co-administration of peptone and crokidolite, 25.6% following 12 months of crokidolite injection, and 72.1% after use of crokidolite alone. The effect of peptone administration is accounted for by the action of macrophages on transformed mesothelial cells and mesothelioma cells.

A comparative analysis of the treatment of 120 patients after endoprosthesis for degenerative-destructive diseases of the hip joint was carried on. All the patients were divided into two groups: the main group included 74 patients who underwent a full course of rehabilitation, the control group consisted of 46 patients without rehabilitation. The results of a comparative assessment of the static-dynamic function in the two groups of patients after operation of endoprosthesis have shown the inclusion of an obligatory program of rehabilitation to be expedient for the restorative treatment in addition to the operation of endoprosthesis.

Indirect immunoperoxidase assay and computer analysis of photographic images revealed more intensive expression of prolactin receptors in hepatocytes of women compared to men. The intensity of expression was maximum in secondary liver cancer, high in obstructive jaundice of different etiology, and less pronounced in cholelithiasis. The expression of prolactin receptors in cholangiocytes was higher than in hepatocytes and was maximum during obstructive jaundice of different etiology. Cells of secondary tumors were characterized by low expression, while distant hepatocytes most intensively expressed prolactin receptors.

To investigate the effectiveness of superfrequent transesophageal left atrial stimulation (TLAS) and its combination with cordarone in management of atrial flutter (AF).650 patients with paroxysmal AF underwent TLAS. The paroxysm duration varied from 1 hour to 1 month. In 312 patients TLAS was performed prior to treatment with antiarrhythmic drugs (group 1), in 338 patients--after intravenous administration of cordarone (group 2).Superfrequent TLAS has restored sinus rhythm (SR) in 85(27.2%) and 169(50%) patients of groups 1 and 2, respectively (p0.001). TLAS promoted conversion of AF in atrial fibrillation (AFi) in 185(59.3%) and 159(47.1%) patients of groups 1 and 2, respectively (p0.01). Moreover, SR recovered 24-48 hours after TLAS in 87(27.9%) and 64(18.9%) patients of groups 1 and 2 respectively (p0.01). Sinus rhythm recovered in a total of 172(55.1%) and 233(69.0%) patients, AF was converted to AFi in a total of 88(31.4%) and 95(28.1%) patients (p0.05) of groups 1 and 2, respectively. TLAS was uneffective in 42(13.5%) and 10(2.9%) patients of groups 1 and 2, respectively.Superfrequent TLAS is a highly effective and non-invasive modality in the treatment of paroxysmal AF. It promotes recovery of SR. In some patients TLAS induces AFi which is more controllable by medication as regards the heart rate. Cordarone contributes to the response to TLAS in patients with paroxysmal AF.

To assess by means of transesophageal left atrial pacing the effectiveness of cordarone treatment for arrhythmias caused by re-entry mechanism.Effectiveness of cordarone treatment was estimated in 25 patients with atrioventricular nodal tachycardia (AVNT) and in 33 patients with WPW syndrome and reciprocal atrioventricular tachycardia (RAVT) with frequent paroxysms of tachycardia 1-5 times per week. Transesophageal left atrial pacing (TELAP) was performed before antiarrhythmic treatment and on cordarone treatment day 14-18. Cordarone was given for two months in common regimen (the first 10 days--600 mg/day, the next 10 days--400 mg/day and then 200 mg/day).The first TELAP induced paroxysmal AVNT or RAVT in all the patients. According to the results of the second TELAP, all the patients were divided into three groups. Group 1 included 28 patients in whom the second TELAP was unable to induce tachycardia. All these patients had increased effective refractory period (ERP) of AV node and/or of accessory pathway (AP) values and a decreased Wenkebach point (WP)150/min during the second TELAP in comparison with the first TELAP. All these patients had no spontaneous paroxysms of T during the 3-month follow-up. Group 2 included 18 patients in whom the second TELAP induced AVT lasting30 seconds. 16 of these patients had tachycardia with less heart rate during the second TELAP in comparison with the first TELAP, 153 + (-) 8 bpm vs 188 + (-) 10 bpm, p0.001, respectively. Also, in these 16 patients we found an increase of values of ERP of AV node and/or AP360 ms and a decrease of WP150 bmp. 14 of these 16 patients had no spontaneous paroxysms of AVT and 2 patients had short episodes of AVT during the 3-month follow-up with effects of vagal manoeuvers. From 2 other patients of group 2 one had short episodes of spontaneous T and one had long episodes of tachycardia with effect of verapamil i.v. Group 3 included 12 patients in whom the second TELAP induced the same AVT as the first TELAP. Values of ERP of AV node and/or AP and WP during the first and second TELAP were not different. All of these patients had long spontaneous paroxysms of AVT during cordarone treatment day 14-18. The treatment was discontinued in all patients of group 3.Cordarone is effective in prevention of AVT. Negative results in provocation of AVT during TELAP after 14-18 days of cordarone treatment is a very specific predictor of cordarone treatment effectiveness. Provocation by TELAP of short episodes of AVT with reduced heart rate and higher values of ERP of AV node and AP and lowering of WP150 bpm may not predict ineffectiveness of cordarone in patients with AVT. Moreover, the majority of these patients had no spontaneous episodes of AVT. Provocation by TELAP during cordarone treatment of the same AVT episodes as before cordarone treatment is a very specific predictor of cordarone effectiveness.

A new Taq I polymorphism in Alu repeat 4 of the human factor IX gene is reported. This polymorphism is associated with a C-T transition at the 72-bp position of the Alu repeat consensus sequence. A simple PCR system for testing of this structural anomaly, with internal control of restriction hydrolysis, was developed. The frequency of the new polymorphic site and its linkage with other polymorphisms of the factor IX gene were also evaluated. The new polymorphism was used for establishing hemophilia B carriers.

Formation of dependence on sex of the unusual estrogen-binding protein (UEBP) expression in rat liver during postnatal development was studied using radioligand and immunohistochemical techniques. UEBP was shown to appear in the male and female liver by day 45 to 50 of postnatal life. In females, UEBP remained at a low level until day 75 to 80, corresponding to faint UEBP-specific staining of a single layer of hepatocytes surrounding the central vein. Thereafter UEBP level decreased below the resolving capacity of the method. In males, UEBP content progressively increased during subsequent stages of ontogenesis. This is accompanied by formation of a stable descending centrolobular-periportal gradient of UEBP-positive hepatocytes. High UEBP expression in the male liver was found to result from the programming effect of androgens exerted between days 1-3 and 12 of postnatal development. The formation of hepatic lobuli is not a condition sufficient for switching on the androgen program of UEBP expression. The absence of testicular androgens in males after day 12 of life does not affect the androgen-programmed ontogenetic time course of UEBP expression at high levels. Experimental programming of UEBP expression in hepatocytes of immature females with the use of androgens results in lower UEBP levels than in males. These levels are comparable to those found in male liver at early stages of regeneration (96 h) after partial hepatectomy. It is suggested that androgens determine not only UEBP-producing capacity of hepatocytes but also the system of its control.

We demonstrate that on the rat liver, testosterone (T) induced differentiated functions and enhanced unusual estrogen-binding protein (UEBP) content through mechanisms dependent on cell activation by androgens, the presence of growth hormone (GH) and the hormonal status of the animal. To determine whether liver cells are a target for androgens, we measured T effects of UEBP in gonadectomized adult male and female rats in vivo and in vitro. In ovariectomized rats, T increased 8- to 9-fold UEBP levels that remained constant during 10 days. Also in vitro, using hepatocytes from ovariectomized rats, T alone increased UEBP levels 3-fold in a dose-response pattern. Combining a fixed low dose of GH with different concentrations of T increased UEBP 2-fold above T alone. Whereas GH alone had no effects in ovariectomized rats, hepatocytes were responsive to GH, in a dose dependent pattern that was abolished when T was used together with GH. On the other hand, T alone had no effect in hypophysectomized-ovariectomized animals. The latter group was rendered T responsive after the simultaneous injection of GH with T that increased UEBP content 6.6-fold in vivo. Castrated males revealed a marked responsiveness to T and GH in vivo and in vitro, when added separately or in combination. The results obtained suggest a complex regulatory system and we conclude that T acts directly on rat liver as: (1) an inducer of sex differentiation; and (2) a regulator of UEBP production in males. In addition, liver regeneration studies in castrated-hypophysectomized males revealed the UEBP phenotype in daughter cells in the absence of treatment. These findings provide novel insights in eukaryotic systems where a T-imprinted phenotype continued to be expressed after withdrawal of hormonal determinants.

The content of androgen receptors (AR) in the cytosol and nuclear fractions of rat liver cells was studied by using the radioligand method. It was found that the nuclear AR content depends on the sex of animals as well as on the initial level of AR in the cytosol fraction. Elevation of AR concentration (p less than 0.05) in liver nuclei of different groups of animals was noted one hour after injection of 100 micrograms of methyltrienolone (R-1881). This elevation correlated positively with the initial level of AR in the cytosol. The accumulation of AR in liver nuclei was more pronounced in intact males than in females. A direct positive correlation between the initial level of cytosol AR and the final regulatory effect of androgens on the hepatic AR content (r = 0.955, n = 6, p less than 0.02) and on the content of the hepatic unusual estrogen-binding protein (UEBP) (r = 0.957, n = 9, p less than 0.001) were found. It is concluded that androgens induce in liver nuclei the accumulation of AR whose level correlates with that of the initial cytosolic AR. The latter reflects the efficiency of the direct effect of androgens on liver cells.

The content of unusual estrogen-binding protein (UEBP), the level of DNA and common protein as well as the organ mass were studied over time during regeneration of the rat liver of intact males and gonadectomized males and females. In 21 days after partial hepatectomy of males with intact testes complete restoration of the UEBP content was observed simultaneously with restoration of the DNA and protein levels and the organ mass. There was no temporary decline of the UEBP content per DNA unit at the early stages of regeneration. The UEBP content in the liver grows during regeneration with the elevation of the DNA level not only in males with intact testes but also in preliminarily castrated males. Different UEBR programs were revcaled by the 21st day of liver regeneration in preliminarily gonadectomized animals: the androgen program of the elevated UEBP content in males, and the basal genetic program of the low level of UEBP expression in females. A conclusion has been made that the hormonal memory of a high UEBP content may be transferred to a new generation of hepatocytes in the absence of androgens. It has been assumed that androgens cause the real determination of masculinization of the EUBP content in liver cells.

The theoretical basis of this work is the development of autosensitization in exposure to ionizing radiation and well-known desensitizing action of sulphuric agents. To reduce clinical manifestations of a reaction to combined radiotherapy 34 women with diagnosis of cervical cancer (stages I and II) were given 0.5-1 g of purified sulphur mixed with 0.25 g of glucose in the morning every 2-3 hours before irradiation, per os; 24 patients received placebo (a mixture of egg powder with glucose), in 21 patients no protective means were used. All 79 patients were given unified adjuvant therapy (polyvitamins, leukogens, folic acid) and diet No 15. A significant decrease in the reaction to therapeutic irradiation was noted in the study group. No side-effects were observed.

The role of the pituitary gland was investigated in the regulation of the level of rat liver androgenic receptors (AR) and in the realization of polydifferentiating action of gonadal hormones. The level of AR in the female and male rat liver was shown not to depend directly on the presence of the pituitary gland or STH administration. The pituitary gland is not a mediator in the realization of polydifferentiating action of androgens and estrogens. STH enhances the development of a positive effect of androgens on the level of AR.

A study was made of the specificities of polydifferentiating action of androgens (A) and estrogens (E) on the level of androgen receptors (AR) of the rat liver cytosol. Androgen receptors were shown to be detected in the neonatal period of ontogenesis, their level was progressively on the increase with the body development. Sex differences in their content were revealed in mature animals only. The AR level is a reversibly controlled, but unprogrammed sex-related sign. The effects of sex steroids are dose-related and modulated reciprocally by the action of endogenous A and E. The action of physiological doses of A and E is characterized by slow development of the effect. Correlation between the level of AR and the efficacy of A action on the content of these proteins was revealed.

Distinct and stable decrease of testosterone content was found in blood serum of one month old rats with burns of the IIIA-IIIB degree impairing 23-25% of body surface. Concentration of androgene receptors was markedly decreased in liver cytosol of the experimental animals within 1 day and to the end of the first week after the thermic trauma. Possible mechanisms involved in impairment of androgene-dependent regulation of metabolism under conditions of thermic burns are discussed.

The direct effect of estradiol (E2) on the hepatocytes of mature male rats has been examined by measuring the changes in the unusual estrogen-binding protein (UEBP) content and parallel measuring the level of liver estrogen receptors (ER). The content of UEBP (NUEBP) and ER (NER) in the liver were determined using the quantitative methods for differential specific determination of the E2-binding sites of these proteins. It has been shown that the administration of E2 in vivo induced a considerable decrease in hepatic NUEBP not only in intact males, but also in hypophysectomized males during the initial period after the operation (when the content of hepatic ER was still high) and produced no effect in hypophysectomized males during the later period (when liver ER were depleted). Repeated administration of human growth hormone (hGH) (twice a day) resulted in a considerable increase in NER in hypophysectomized males and restored the sensitivity to the subsequent inhibitory effect of E2 on UEBP. We also used rat hepatocytes after a 4-day primary culturing. These cells had a stable morpho-functional status, high ER level, and sex-differentiated UEBP content. Culturing of mature male rat hepatocytes in the medium containing E2 at concentrations close to physiological levels (10(-10)-10(-7) M) decreased NUEBP in a dose-dependent manner. Hexestrol (10(-7) M) but not cholesterol (10(-5) M) also exhibited a direct effect on NUEBP in cultured rat hepatocytes. The effect of E2 was reversible: statistically significant increase in NUEBP was observed 3 days after 10(-9) M E2 had been removed from the culturing medium. It was concluded that hepatocytes may be a primary target for E2 under physiological conditions and that GH may modulate the direct effect of E2 at the hepatic level by modifying the content of liver ER.

1. Administration of insulin does not significantly affect the level of SEBP in the livers of male rats. 2. Adrenalectomy and administration of dexamethasone do not cause any pronounced changes in the sexual differentiation of the SEBP content in the liver. 3. Administration of physiological doses of T3 produces a dose-dependent and reversible decrease in the level of SEBP in the livers of sexually mature male rats, and also decreases the degree of induction of this protein by androgens in the livers of females. 4. The action of T3 does not significantly depend on the sex hormones and pituitary factors. 5. Administration of STH raises the level of SEBP in the liver only in hypophysectomized males but not in intact or castrated males.

Liver cytosol of mature male rats was found to contain androgen receptors (AR). These AR were purified 7--10-fold, and their molecular and hormone-binding properties were investigated. It was found that the AR molecules have a sedimentation coefficient of 9.3 +/- 0.15 and 4.7 +/- 0.11 S, Stokes radius of 6.5 +/- 0.25 and 3.2 +/- 0.08 nm, Mr of 263000 and 65700 Da and friction coefficient ratio of 1.55 and 1.22 for low and high ionic strength media, respectively. The values of rate constants of [3H]methyltrienolone (R1881) association with AR and for the dissociation of the complexes formed are equal to (0.66 +/- 0.29). .10(5) M-1 s-1 and to (0.68 +/- 0.08).10(-5) s-1, respectively, whereas those of equilibrium association constant--to (1.4 +/- 0.3).10(9) M-1 at 0-4 degrees C. It was shown that R1881, 5 alpha-dihydrotestosterone and testosterone strongly compete with 3H-R1881 for the binding with AR (as can be judged from the relative competitive activity of 35 nonlabeled hormonal agents); 19-nortestosterone and delta1-testosterone are more weak, whereas 5 alpha-androstandiols, some hydroxy derivatives of testosterone, cyproterone acetate, estradiol and progesterone are moderate competitors. Other natural testosterone, estradiol and progesterone metabolites as well as corticosteroids do not compete or weakly compete with 3H-R1881 for the binding to AR. It is concluded that the properties of AR are similar to those of classical type AR and that they can intermediate most of the direct effects of androgens on the liver.

Some properties of the macromolecules of the KCl-extracts of the nuclei of the uterus, kidney, liver, testis and prostate, specifically binding estradiol (E2), were studied. These macromolecules of the uterus and the liver were found to be maximally extracted from chromatin by the 0.6 M KCl concentration. The capacity of the macromolecules of the uterine, kidney and liver nuclear extracts to bind E2 specifically is destroyed completely by pronase, but not by RNA-ASe and DNA-ase, pointing to the protein nature of these macromolecules. Only estrogenic compounds, but not testosterone, 5alpha-dihydrotestosterone, progesterone or corticosterone were capable to compete with H3--E2 for the E2--binding sites of the macromolecules of the nuclear extracts of all the organs investigaeted. It is assumed that macromolecules of the nuclei of the investigated nontarget organs specifically binding E2 are estrogen receptors.

Forms I and II of the estrogen receptors of female rat liver were isolated by desalting of the cytosol fraction desalting with 40% saturated (NH4)2SO4 with a subsequent gel-filtration through Ultragel AcA 44. In the absence of 0,3 M NaCl form I produces heavy aggregates and is eluted from Sepharose 6B in excluse volume. The molecular weight of from II under the same conditions as measured during gel-filtration and gradient centrifugation is 80 000. In the presence of 0,3 M NaCl the molecular weights of forms I and II are 63 000 and 77 000, respectively. The pH optima for the estradiol-binding activity of forms I and II are 6,8--8,5 and 7,4--9,1, respectively. Form II is more stable to heating and storage at 4 degrees. The binding activity of both forms of the receptors is eliminated by p-chloromercurybenzoate. The equilibrium constant for form II association with estradiol exceeds that of form I 2,5-fold and is equal to 2,4 x 10(10) M-1. The presence of 0,3 M NaCl does not affect this parameter in both cases. The association of forms I and II with estradiol and dissociation of the complexes are of a two-step type. The k+1 values for forms I and II are identical, whereas the k-1 value for form I is about two times that for form II. In terms of their competitive activity the hormone compounds tested can be arranged in the following order: estradiol less than or greater than hexestrol much greater than estrone congruent to estriol congruent to 17-deoxyestradiol much greater than 5 alpha-dihydroxytestosterone congruent to testosterone. Progesterone and corticosterone do not reveal competitive properties. The functional similarity of forms I and II of estrogen receptors from rat liver suggests that these proteins are isoreceptors.

A new modification of specific estrogen-binding protein (SEBP) assay in the liver was used to measure the content of this protein at different stages of ontogenesis in male and female rats after administration of testosterone propionate (TP). It was shown that liver capability to form SEBP could be initially programmed by androgens. The crucial period of the SEBP-determining action of androgens in females is not restricted, since potential capability of androgens of primary induction of SEBP may be realized both neonatally and in the course of pubertation. The emergence of SEBP in the liver of males may be the result of natural pre(neo)natal androgenization. Androgens do not play any decisive role in the control of the level of induced SEBP, inasmuch the content of SEBP in the liver of non-pubertal and pubertal males does not appreciably change after TP administration but grows with pubescence. SEBP is capable of long-term existence in the absence of androgens. The presence of the ovaries produces an inhibitory effect on the level of androgen-induced SEBP and the time of its existence after TP discontinuation. Hypophysectomy does not provoke SEBP emergence in pubertal intact and ovariectomized females but prevents its induction with androgens. Adrenal- and thyroectomy produce no influence on the SEBP-programming effect of TP or promote its spontaneous appearance in the same groups of female rats.