Biomedical subjects

I Cavarretta

Publications and source records attributed to I Cavarretta.

11 recordsLinked to original sources

PubMed2000

Testosterone metabolites in patients reduce the levels of very long chain fatty acids accumulated in X-adrenoleukodystrophic fibroblasts.

Testosterone metabolites (dihydrotestosterone, DHT) and 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol), but not testosterone itself, were shown to reduce the levels of very long chain fatty acids which accumulate in cultured skin fibroblasts from X-adrenoleukodystrophic patients (X-ALD). In addition, in X-ALD fibroblasts, testosterone is less actively converted into DHT vs. controls (skin fibroblasts retrieved from normal subjects) whereas the additional conversion of DHT to the final product 3 alpha-diol is enhanced. This is the first report of altered testosterone metabolism in X-ALD fibroblasts and of the effects of androgens in lowering the abnormal accumulation of very long chain fatty acids in this type of cells.

Adrenoleukodystrophy↗

PubMed1999

Po gene expression is modulated by androgens in the sciatic nerve of adult male rats.

The present results show that androgens are able to modulate the Po gene expression in different models. In particular, we have shown that: (1) the messenger for the androgen receptor (AR) is present in the rat sciatic nerve but not in cultured Schwann cells; (2) castration induces a decrease of Po mRNA levels in the sciatic nerve of male rats, which is counteract by the subsequent treatment with dihydrotestosterone (DHT), the 5alpha-reduced metabolite of testosterone; (3) castration is also able to significantly decrease in the sciatic nerve the activity of the enzyme 5alpha-reductase (which converts testosterone into DHT); and (4) DHT is able to stimulate Po gene expression in cultured Schwann cells. These observations seem to indicate that androgens may exert their effect on Po gene expression via indirect mechanisms; modulation of neuronal influences reaching the Schwann cells through the binding of the androgen to the AR present in neurons may be postulated. However, alternative mechanisms may also be taken in consideration. The data presented suggest indeed that androgens might act on Schwann cells via the progesterone receptor (PR) rather than the AR. It has been observed that: (1) the messenger for PR is present in Schwann cells; (2) DHT may activate the transcriptional activity of a PR-responsive gene by binding to the PR; and (3) putative steroid responsive elements have been described in this paper to be present in the Po promoter region.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1999

Progesterone derivatives are able to influence peripheral myelin protein 22 and P0 gene expression: possible mechanisms of action.

The present study has analyzed the effect of progesterone and its derivatives (dihydroprogesterone and tetrahydroprogesterone) on the gene expression of the peripheral myelin protein 22 utilizing in vivo and in vitro models. The data obtained indicate that tetrahydroprogesterone is able to stimulate the gene expression of peripheral myelin protein 22 both in vivo (in adult but not in old animals) and in Schwann cell cultures. An effect of this steroid, which is known to interact with the GABA(A) receptor, would not be surprising, since in the present study we show the presence in Schwann cells and in the sciatic nerve of the messengers for several subunits (alpha2, alpha3, beta1, beta2, and beta3) of the GABA(A) receptor. An effect of tetrahydroprogesterone is also evident on the gene expression of another myelin protein, the peripheral myelin protein zero. However, in this case also dihydroprogesterone, which is able to bind the progesterone receptor, is involved, both in old and adult animals, in the stimulation of messengers levels of this myelin protein. In conclusion, the present data show that the gene expression of two important peripheral myelin proteins can be influenced by progesterone derivatives. The hypothesis has been put forward that part of their effects might occur not through the classical progesterone receptor, but rather via an interaction with the GABA(A) receptor.

20-alpha-Dihydroprogesterone↗

PubMed1999

Interactions between type 1 astrocytes and LHRH-secreting neurons (GT1-1 cells): modification of steroid metabolism and possible role of TGFbeta1.

The hypothesis that type 1 astrocytes (A1) might modify the activities of the enzymes 5alpha-reductase (5alpha-R) and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) present in the GT1-1 cells has been tested. The data obtained indicate that, utilizing a co-culture technique, A1 are able to: (1) decrease the formation of dihydrotestosterone (DHT) from testosterone (T); (2) increase the formation of dihydroprogesterone (DHP) from progesterone (P); (3) decrease the conversion of DHP into tetrahydroprogesterone (THP) in GT1-1 cells. Moreover, GT1-1 cells are able to increase the formation of DHP in A1; that of DHT was unchanged. The present data might suggest the possible existence of a third isoform of the enzyme 5alpha-R; details on this hypothesis are provided in the text. Interestingly, the inhibitory effect exerted by A1 on the formation of DHT in GT1-1 cells can be mimicked by transforming growth factor beta1 (TGFbeta1). Since TGFbeta1 had been previously shown to be directly involved in the stimulatory control of LHRH secretion by GT1-1 cells, acting both on LHRH release [R.C. Melcangi, M. Galbiati, E. Messi, F. Piva, L. Martini, M. Motta, Type 1 astrocytes influence luteinizing hormone-releasing hormone release from the hypothalamic cell line GT1-1: is transforming growth factor-beta the principle involved? Endocrinology 136 (1995) 679-686.] and gene expression [M. Galbiati, M. Zanisi, E. Messi, I. Cavarretta, L. Martini, R.C. Melcangi, Transforming growth factor-beta and astrocytic conditioned medium influence LHRH gene expression in the hypothalamic cell line GT1, Endocrinology 137 (1996) 5605-5609], the present data also show that TGFbeta1 might intervene in modulating feedback signals reaching hypothalamic LHRH producing neurons. The present findings underline once more the importance of the physiological cross-talk between A1 and neurons.

20-alpha-Dihydroprogesterone↗

PubMed1998

Age-induced decrease of glycoprotein Po and myelin basic protein gene expression in the rat sciatic nerve. Repair by steroid derivatives.

The data here reported show that the gene expression of the glycoprotein Po and of the myelin basic protein, the major components of myelin in the peripheral nervous system, dramatically decreases with ageing in the sciatic nerve of normal male rats. A one-month treatment with dihydroprogesterone, the 5alpha-reduced derivative of progesterone, is able to partially restore the fall in Po gene expression occurring in the sciatic nerve of aged male rats, without significantly modifying the gene expression of the myelin basic protein. In cultures of neonatal Schwann cells (the peripheral nervous system elements involved in the synthesis of myelin), the addition of progesterone and of dihydroprogesterone significantly increases Po gene expression; the 3alpha-reduced metabolite of dihydroprogesterone, tetrahydroprogesterone proved to be even more effective. These data suggest that the effect of progesterone is linked to its conversion into dihydroprogesterone and especially into tetrahydroprogesterone, since Schwann cells possess the 5alpha-reductase-3alpha-hydroxysteroid dehydrogenase system. The data provide the first demonstration that ageing decreases the gene expression of two major components of the peripheral myelin in the sciatic nerve; they also show that this phenomenon may be partially reversed by progesterone derivatives, which might act by stimulating Po gene expression in the Schwann cells.

20-alpha-Dihydroprogesterone↗

PubMed1998

The 5alpha-reductase in the central nervous system: expression and modes of control.

The present paper will summarize two important aspects of the interactions between steroids and the brain, which have recently been studied in the authors' laboratory. In particular the paper will consider data on: (1) the significance of the two isoforms of the 5alpha-R during brain ontogenesis and development, and (2) the cross-talk between glial and neuronal elements, particularly in relation to the metabolism of sex hormones. (1) The data obtained have shown that the 5alpha-R type 1 enzyme is constitutively expressed in the rat CNS at all stages of brain development. Moreover, the expression of the 5alpha-R type 1 is similar in males and in females, and does not appear to be controlled by androgens. The gene expression of the 5alpha-R type 2 is totally different. This isoform appears to be expressed in the rat brain almost exclusively in the late fetal/early post-natal life and is controlled by testosterone. (2) The present data show that two cell lines derived respectively from a rat glioma (C6 cell line) and from a human astrocytoma (1321N1 cell line) are able to convert testosterone and progesterone into their corresponding 5alpha-reduced metabolites dihydrotestosterone and dihydroprogesterone. The possibility that secretory products of normal and tumoral brain cells might be able to influence steroid metabolism occurring in the two glial cell lines previously mentioned has been considered.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1998

Crosstalk between normal and tumoral brain cells. Effect on sex steroid metabolism.

The present article shows for the first time that two cell lines derived respectively from a rat glioma (C6 cell line) and from a human astrocytoma (1321N1 cell line) are able to convert testosterone and progesterone into their corresponding 5 alpha-reduced metabolites dihydrotestosterone and dihydroprogesterone. Moreover, both cell lines are also able to convert these metabolites further into their corresponding 3 alpha-OH derivatives, 5 alpha-androstan-3 alpha, 7 beta-diol (3 alpha-diol) and tetrahydroprogesterone. On the basis of these observations, the possibility that secretory products of normal and tumoral brain cells might be able to influence steroid metabolism occurring in the two glial cell lines previously mentioned as well as in fetal rat neurons and in neonatal rat type 1 astrocytes has been considered. To this purpose, cultures of the different cellular types have been exposed to the conditioned medium in which the other cells were grown. The results obtained indicate that: 1. Neurons are able to stimulate, in a statistically significant fashion, the formation of dihydrotestosterone (DHT), 3 alpha-diol, and tetrahydraprogesterone (THP) in C6 cells. 2. Type 1 astrocytes, on the contrary, are unable to modify steroid metabolism in C6 cells. 3. C6 cell product(s) decrease(s) the formation of DHP in type 1 astrocytes, without modifying that of DHT. 4. C6 cells do not influence the metabolism of testosterone (T) and progesterone (P) in neurons. In conclusion, the present observations show that the conditioned medium of normal neurons is able to increase the metabolism of testosterone and progesterone occurring in a tumoral glial cell line, and that the conditioned media of the two tumoral cell lines analyzed are able to decrease the conversion of P into DHP occurring in normal type 1 astrocytes. The surprising result that these conditioned media do not alter the formation of DHT is discussed. Work is presently in progress to identify the principle(s) responsible respectively for the activating and inhibiting actions here described.

20-alpha-Dihydroprogesterone↗

PubMed1997

Astrocyte-neuron interactions in vitro: role of growth factors and steroids on LHRH dynamics.

The data here reviewed, obtained with in vitro models, indicate that growth factors and steroids play a significant role in astrocyte-neuron interactions. Different designs have been adopted: (1) GT1-1 cells (a cell line derived from a mouse hypothalamic LHRH-producing tumor) were cocultured with type 1 rat astrocytes; and (2) GT1-1 cells were exposed to the conditioned medium (CM) in which type 1 rat astrocytes had been grown for 24 h. LHRH release and mRNA LHRH levels were measured respectively in the medium and in cell homogenates, at different time intervals (LHRH release, by RIA; LHRH mRNA by Northern blot analysis). The data obtained show that type 1 astrocytes secrete in the medium TGFbeta, which is able to modulate the release and the gene expression of LHRH in GT1-1 cells; and that one or more LHRH-degrading enzymes is/are present in the conditioned medium of type 1 astrocytes. A second part of the experiments have indicated that type 1 astrocytes are also able to affect, in different directions, the metabolism of testosterone and progesterone into their 5alpha-reduced metabolites occurring in the GT1-1 cells. In particular, it has been observed that the conversion of testosterone into DHT is decreased by the coculture with type 1 astrocytes, while the conversion of progesterone into DHP is increased by the same coculture conditions. Moreover, type 1 astrocytes are sensitive to steroid hormones, and in particular to the 5alpha-reduced metabolites of progesterone; this has been shown by analyzing the effects exerted by different steroids on the gene expression of the typical astrocyte marker GFAP.

Animals↗

PubMed1997

Corticosteroid effects on gene expression of myelin basic protein in oligodendrocytes and of glial fibrillary acidic protein in type 1 astrocytes.

The paper describes the effects of corticosterone and deoxycorticosterone (DOC), used in their native or in their 5 alpha-reduced molecular forms (dihydrocorticosterone, DHC; dihydrodeoxycorticosterone, DHDOC; and tetrahydrodeoxycorticosterone, THDOC) on the gene expression of the myelin basic protein (MBP) and of the glial fibrillary acidic protein (GFAP) in pure cultures, respectively, of oligodendrocytes and type 1 astrocytes obtained from the neonatal rat brain. Among the different steroids tested (corticosterone, DHC, DOC, DHDOC and THDOC), only DHDOC was effective on the gene expression of MBP in the oligodendrocyte cultures; the mRNA levels of this typical oligodendrocyte marker were decreased following exposure to this steroid for 24 h. In the case of the astrocytic marker GFAP, its gene expression was increased by the exposure to corticosterone for 6 and 24 h, while DHC was ineffective; the mineralocorticoid DOC was also ineffective, while its 5 alpha-reduced derivative, DHDOC, strongly inhibited GFAP gene expression, starting at 6 h after beginning of the treatment. In conclusion, the present data show that: (1) adrenal steroids possessing gluco- and mineralocorticoid activities may influence the gene expression of the astrocytic marker GFAP; (2) the 5 alpha-reduced metabolite of DOC, DHDOC is able to influence the gene expression not only of GFAP but also that of MBP, which are, respectively, typical markers of the astrocytes and the oligodendrocytes; (3) the metabolic conversion of hormonal steroids into their 5 alpha-reduced metabolites, which also occurs in the glia, could be implicated in the biochemical control of oligodendrocyte and astrocyte functions.

Adrenal Cortex Hormones↗

PubMed1996

Transforming growth factor-beta and astrocytic conditioned medium influence luteinizing hormone-releasing hormone gene expression in the hypothalamic cell line GT1.

On the basis of our previous observations indicating that a principle [possibly transforming growth factor-beta1 (TGFbeta1)] secreted by type 1 astrocytes may increase the release of LHRH in the GT1 cell line, it was deemed of interest to analyze whether TGFbeta1 might influence LHRH gene expression in addition to LHRH release in GT1-1 neurons. The effects of TGFbeta1 on the levels of LHRH messenger RNA (mRNA) present in GT1-1 cells have been compared to those found after either coculture of these cells with type 1 astrocytes or exposure of GT1-1 cells to the conditioned medium in which type 1 astrocytes were grown for 24 h. The data obtained indicate that 1) TGFbeta1 increases LHRH mRNA levels 1 and 6 h after the beginning of treatment; longer exposures (24 h) bring about a decrease in LHRH gene expression; 2) a significant stimulatory effect of TGFbeta1 (1 and 6 h of exposure) is also evident on LHRH release; 3) the exposure to the conditioned medium of type 1 astrocytes is able to increase LHRH gene expression in GT1-1 cells at 1 h; LHRH mRNA levels show a small decrease after 6 h of exposure, which becomes more evident at 24 h; and 4) the coculture of GT1-1 cells with type 1 astrocytes is not able to modify LHRH mRNA levels at any time considered. The present data support the concept that glial cells are able to control, possibly through the release of TGFbeta, the gene expression of LHRH in hypothalamic neurons.

Astrocytes↗

PubMedDate not supplied

Effects of steroid hormones on gene expression of glial markers in the central and peripheral nervous system: variations induced by aging.

The present article summarizes our data regarding: (a) the effect of sex steroids on the expression of a specific astrocytic marker in glial cell cultures (GFAP); (b) the effects of aging on two markers of the peripheral myelin (glycoprotein Po and the myelin basic protein, MBP); (c) the possible modification of the damaging effects of aging on these two markers by the in vivo administration of progesterone and its derivatives; and, finally, (d) the effect of progesterone derivatives on the gene expression of Po in cultures of rat Schwann cells. The data obtained have indicated that progesterone and its 5 alpha-reduced metabolites may play an important role in the control of gene expression of GFAP and Po, respectively, in type 1 astrocytes and Schwann cells. It has also been found that the gene expression of Po and MBP is dramatically decreased in the myelin of the sciatic nerve of aged male rats and that the aged-linked decrease of the gene expression of Po is partially reversible with steroid treatment.

Aging↗