Molekulska osnova delovanja glikokortikoida

Glucocorticoid hormones are involved in regulation of cell processes and coordinate physiological response to diverse signals. These hormones, through interaction with specific intracellular receptors, coordinate components of physiological repertoires by activating the expression of gene networks. Thus hormone-receptor complexes may function as key constituent in regulation of specific cell functions as well as in provoking differentiation in already determined cells. Analysis of steroid receptors are important for understanding of molecular details of transcriptional control as well as providing the insight as to how an individual transcriptional factor such as glucocorticoid receptor, contributes to cell identity and function. The purpose of this review is to establish the general molecular mechanism of glucocorticoid action and mechanism associated hormone-receptor complexes with the control of differential patterns (i.e. "positive" and "negative") of gene expression. One of the examples of two signal pathways regulating opposite gene expression are NF-kB and GR-mediated signal pathways. These pathways have important and opposite roles in the immune function. NF-kB is transcription factor which induces the expression of many genes that participate in immune and inflamatory response, while GR is transcription factor that serves as antiinflammatory agent and immune suppressor. Their interactions within the cell, although not yet completely understood, appear to be an important, possibly even the primary mechanism of immune homeostasis. It has not been established that glucocorticoid sensitivity can be caused by mechanisms other than changes of GR number and properties, although recent studies have indicated that receptor isoforms and transcriptional factors may modulate glucocorticoid responsiveness by interacting with receptor protein or directly at the site of DNA binding. The aim of this review is also to describe the role of glucocorticoid receptors in mechanism of glucocorticoid action on cell functions, including immune responses, as well as to present emerging issues on clinical aspects of molecular mechanisms of glucocorticoid action.Glikokortikoidni hormoni su uključeni u regulaciju ćelijskih procesa koji koordiniraju fiziološke odgovore na različite signale. Ovi hormoni u kompleksu sa specifičnim ćelijskim receptorima preko aktivacije ekspresije mreže različitih gena učestvuju u koordinaciji komponenti koje su u osnovi fizioloških odgovora. Na taj način kompleksi hormona i receptora funkcionišu kao ključni faktor u regulaciji specifičnih ćelijskih funkcija, a takođe podstiču i procese diferencijacije u već determinisanim ćelijama. Analize glikokortikoidnih receptora (GR) su značajne, kako za bolje upoznavanje transkripcione kontrole, tako i za objašnjenje kako pojedini transkripcioni faktori, kao što su GR, doprinose identitetu ćelije i njenom funkcionisanju. U ovom radu su prikazani opšti principi molekulskog mehanizma delovanja glikokortikoida, kao i mehanizmi koji povezuju komplekse hormona i receptora sa kontrolom različitog tipa („pozitivnom” ili „negativnom”) genske ekspresije. Jedan od primera za signalne puteve koji suprotno regulišu aktivnost gena su nukleusni faktor kapaB (NFκB) i signalni putevi posredovani sa GR. Ovi putevi imaju suprotne uloge u regulaciji funkcionisanja imunskog sistema. NFκB je transkripcioni faktor koji indukuje ekspresiju gena uključenih u imunske i zapaljenjske procese. GR je takođe transkripcioni faktor, ali deluje kao antiinflamacioni i imunosupresivni agens. Njihove interakcije su značajne u ćelijama imunskog sistema, iako još nisu potpuno objašnjene; one su možda čak i primarne u mehanizmu imunske homeostaze. Do sada nije dokazano da ćelijska senzitivnost na delovanje glikokortikoida zavisi od mehanizama koji ne uključuju promene količine i funkcionalnih osobina GR. Međutim, novija istraživanja pokazuju da izoforme receptora i transkripcioni faktori mogu da menjaju ćelijski odgovor na glikokortikoide preko interakcije sa receptornim proteinom ili direktno sa mestima vezivanja na DNK. U ovom radu su takođe prikazani podaci iz literature o ključnoj ulozi glikokortikoidnih receptora u mehanizmu delovanja glikokortikoida u regulaciji ćelijskih funkcija, uključujući i ćelije imunskog sistema, kao i podaci o kliničkim aspektima molekulskog delovanja glikokortikoida

Biochemical and molecular biological aspects of glucose intolerance in elderly persons

Changes in carbohydrate metabolism in elderly persons have drawn considerable attention but the findings from different studies are in contrast and are even controversial. The insulin receptors in erythrocytes were studied in elderly euglycaemic patients and in a middle-aged control group. The examined persons were also subjected to measurements of blood glucose, insulin and C-peptide concentrations, before and 3 hours after a dietetic meal. In the present study it was found that in spite of the maintained insulin level and C-peptide secretion, some structural and corresponding changes in membrane insulin receptors and the binding site caused differences in postreceptor responses in elderly persons. The examined groups, consisted of 29 males, average age of 66 years (65-70), with normal serum glucose level and 19 middle-aged males, average age of 42 years (32-48), with normal glycoregulation. In basal condition, elderly persons have both normal morning serum insulin (19.68 ± 4.00 mU/L) and C-peptide (2.04 ± 0.78 nmol/L) level. In elderly persons, the number of high affinity insulin receptors in erythrocytes membrane is 22.80 ± 6.18 but the formed insulin-high affinity receptors were not stable. Dissociation constant (Kd1) indicates its elevated dissociation (0.11 ± 0.04). At the same time the number of insulin low affinity binding sites is increased (13 273 ± 5 572) with a fast dissociation of the hormone (13.99 ± 3.37). Food intake raised the number of high affinity receptors compared to the basal value. Alteration in insulin binding affinity suggests the structural and corresponding changes in membrane receptors that may cause differences in postreceptors responses in elderly persons

Sex steroid receptors in transformed human cervical tissue.

Investigation of the binding affinity, the concentration and the DNA binding ability of the sex steroid receptors in transformed human cervical tissue has shown considerable changes in comparison to normal specimens. Lower level of hormone receptors and higher dissociation constants are the essential characteristics of the majority of analysed transformed tissue specimens. The DNA binding of steroid-receptor complexes is in agreement with mentionated data. These preliminary results are just one more evidence on the existence of relationship between modified properties of sex steroid receptors and different histological alterations of their target tissues. Further investigations are necessary to make some conclusion about the possible involvement of estrogen and progesterone receptors in pathological transformation of the portio vaginalis uteri

Efekti ćelijske lokalizacije receptora za progesteron na aktivnost RNK polimeraza

8th Yugoslavian Congress of Nuclear Medicine, Kragujevac, Serbia and Montenegr

Promene steroidnih receptora u toku histopatoloske transformacije tkiva humanog uterusa

Estrogen (ER) and progesterone receptors (PR) were analyzed in the cytosol and nuclei prepared from specimens of human uterine tissue of patients with certain disorders identified as hyperplasia endometrii adenomatosa, myoma uteri per magnum, adenocarcinoma endometrii and adenocarcinoma corporis uteri. These investigations have revealed a different level of ER and PR in analyzed tissue specimens, as well as the existence of a relationship between changes in receptor levels and respective Kd. These changes suggest a correlation between steroid receptor levels and the type of tissue transformation. The functionality of the receptors was analyzed by the ultracentrifugation of non-activated and activated steroid-receptor complexes in sucrose density gradients, as well as by the investigation of their interaction with isolated nuclei. These results indicate that some changes in steroid receptor molecules can be detected when the tissue turns from normal to malignant transformation. On the basis of this investigation it could be proposed that the analysis of activated and non-activated steroid-receptor complexes by means of the methods used in this study can be applied as a useful clinical tool in the determination of the endocrine dependence of transformed tissues, as well as for the optimum dosing of individual treatment of patients with uterine and other tissue carcinoma

Alterations in binding of thyroid hormones to serum proteins in patients on regular haemodialysis

Content of triiodothyronine (T3), thyroxine (T4) and thyroid-stimulating hormone (TSH) was determined in the blood plasma of patients with severe renal failure treated by intermittent haemodialysis. Hormone binding to serum proteins was simultaneously analyzed. A decrease in the levels of T3 and T4, as well as an increase in the amount of TSH were observed in all analyzed specimens. However, a significant decline (p<0.025) was detected only in the level of T3 after haemodialysis as compared to the control values. The analysis of hormone binding to serum proteins using agarose gel electrophoresis indicated that higher levels of hormones were bound to albumin in the sera of patients and not of controls. Also a redistribution of hormones binding to albumin and prealbumin occurred in haemodialysis