F. Celotti - Academia.edu (original) (raw)
Papers by F. Celotti
6° Congresso Nazionale dell’Italian Society Space Biomedicine Biotechnology, 2012
Clinical Cancer Drugs, 2016
Background: The importance of epigenetics in cancer is well known. Since many epigenetic mechanis... more Background: The importance of epigenetics in cancer is well known. Since many epigenetic mechanisms are involved in cancer progression, they may represent a target for a new pharmacological approach. Prostate cancer is the most common malignancy in men. After failure of the androgen deprivation therapy, the recurrent disease is termed castration- resistant cancer (CRPC). Since CRPC remains an incurable disease, new studies are focusing on the mechanisms critical for CRPC development, to identify new pharmacological targets. Methods: A MEDLINE research related to CRPC and epigenome has been carried out. Results: CRPC is probably due to several genetic and epigenetic mechanisms involved in AR activation, even in the presence of low androgen levels. Increasing evidence suggests that an aberrant DNA methylation may promote CRPC progression, augmenting genomic instability. Deregulated miRNAs are involved in initiation, progression, and metastatization of prostate cancers. MiRNAs may act like oncogenes (oncomirs) which can promote cancer progression, or tumor suppressors (anti-oncomirs) which inhibit CRPC progression. miRNA replacement therapy represents the most promising anticancer strategy, however only MRX34 (a doublestranded RNA mimic of the anti-oncomir, miR-34) has reached phase I clinical trial. Also, the deregulation of long non coding RNAs (lncRNAs) has been involved in CRPC development and lncRNAs may gain diagnostic/ therapeutic relevance. Recently research was focused on the chromatin reader proteins containing bromodomain and extraterminal domain (BET family). Since BET inhibitors act downstream of AR, these compounds might be effective in a condition of mediated AR resistance to androgen deprivation. Conclusions: The recent finding about CRPC epigenome might provide several emerging treatment strategies to counteract efficiently the tumor progression
It is known that Aromatase (Aro), the enzyme which metabolizes androgens into estrogens, and 5alp... more It is known that Aromatase (Aro), the enzyme which metabolizes androgens into estrogens, and 5alpha-reductase type2 (5\u3b1-R2), which specifically forms DHT, increase their expression and activity in late gestation. We have evaluated, by semiquantitative RT-PCR, the existence of a possible dimorphism of these enzymes during development (from gestational day 16 to postnatal day 5) and some of the factors controlling their expression; in particular, the formation of brain speific Aro transcript (containing Exon If) in comparison with the total expression of this enzyme (including variants differing in the 5'-untranslated regions). It has been observed that Aro has two male-specific peaks of expression, before and after birth and only exon If is used in males, while transcripts other than the brain-specific one are also present in females postnatally. Also the 5alpha-R2 expression is higher in males than in females, particularly just after birth. We can conclude that the sexual differentiation of rodent brain probably involves the activation of both Aro and 5alpha-R2 in a sex- and time-specific pattern
Journal of Steroid Biochemistry, 1987
It is known that the metabolism of testosterone in the brain and in the anterior pituitary is dif... more It is known that the metabolism of testosterone in the brain and in the anterior pituitary is different in mammalian and in photoperiodic avian species. In many mammalian species, testosterone is mainly metabolized to 5-alpha-reduced compounds (e.g. 17-beta-hydroxy-5-alpha-androstan- 3-one, 5 alpha-DHT and 3-alpha,17-beta-dihydroxy-5-alpha-androstane, 5-alpha,3-alpha-diol) and, to a smaller extent, to 4-androstene-3,17-dione (androstenedione), while in birds, androstenedione is the main testosterone metabolite and the conversion to the 5-alpha-reduced compounds is quantitatively negligible. In avian species, testosterone is also converted to 5-beta-reduced steroids (mainly 17-beta-hydroxy-5-beta-androstan-3-one, 5-beta-DHT and 3-alpha,17-beta-dihydroxy-5-beta-androstane, 5-beta,3-alpha-diol), and there is also evidence that in these species testosterone metabolism in the central structures may be influenced by the photoperiod. Since the hamster is a mammal whose reproductive cycle is controlled by day length, it has been analyzed whether: (a) the central structures of the hamster (cerebral cortex, hypothalamus and anterior pituitary) metabolize testosterone in vitro following a mammalian (5-alpha-reduced derivatives) or an avian (androstenedione and 5-beta-reduced compounds) pattern; and (b) the metabolism of testosterone in the same structures may be modified by the exposure to different photoperiods (LD 14:10 or LD 8:16). The present data indicate that no one of the hamster structures examined produces the 5-beta-reduced derivatives. Moreover, the formation of the 5 alpha-DHT is quantitatively low, and is not affected by the photoperiod. In contrast, androstenedione is formed in quite high yields and the exposure of the animals to 60 days of short photostimulation increases the formation of this steroid in the pituitary gland, but not in the brain structures. From these data, it appears that the central structures of the hamster metabolize testosterone with a pattern which is intermediate between that of birds and mammals.
Frontiers in Cell and Developmental Biology, 2015
Epigenetics represents the way by which the environment is able to program the genome; there are ... more Epigenetics represents the way by which the environment is able to program the genome; there are three main levels of epigenetic control on genome: DNA methylation, post-translational histone modification and microRNA expression. The term Epigenetics has been widened by NIH to include "both heritable changes in gene activity and expression but also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable." These changes might be produced mostly by the early life environment and might affect health influencing the susceptibility to develop diseases, from cancer to mental disorder, during the entire life span. The most studied environmental influences acting on epigenome are diet, infections, wasting, child care, smoking and environmental pollutants, in particular endocrine disrupters (EDs). These are environmental xenobiotics able to interfere with the normal development of the male and female reproductive systems of wildlife, of experimental animals and possibly of humans, disrupting the normal reproductive functions. Data from literature indicate that EDs can act at different levels of epigenetic control, in some cases transgenerationally, in particular when the exposure to these compounds occurs during the prenatal and earliest period of life. Some of the best characterized EDs will be considered in this review. Among the EDs, vinclozolin (VZ), and methoxychlor (MXC) promote epigenetic transgenerational effects. Polychlorinated biphenils (PCBs), the most widespread environmental EDs, affect histone post-translational modifications in a dimorphic way, possibly as the result of an alteration of gene expression of the enzymes involved in histone modification, as the demethylase Jarid1b, an enzyme also involved in regulating the interaction of androgens with their receptor.
Journal of endocrinological investigation, 2005
Effects of primary hypothyroidism (HYPO) on the male gonadal axis are controversial, with only sc... more Effects of primary hypothyroidism (HYPO) on the male gonadal axis are controversial, with only scanty data on the gonadotroph cell response and no information on GnRH tuberoinfundibular neurons, even in animal models. HYPO has been reported to variably induce hypogonadotropic hypogonadism, a hypergonadotropic state, or to have no effects on basal levels of pituitary gonadotropins, both in adult male rats and humans. Similarly, the exogenous administration of GnRH to HYPO rats and humans may increase or decrease gonadotropin secretion. Since inhibitory effects of HYPO on the GnRH-gonadotropin axis are reversed by replacement with L-T4, it has been suggested that thyroid hormone (TH) may regulate tuberoinfundibular GnRH and pituitary gonadotropin biosynthesis and/or secretion. To shed light on this hypothesis, we conducted immunocytochemical studies on the distribution and immunostaining characteristics of hypophysiotropic GnRH neurons, LH, PRL and vasoactive intestinal polypeptide (V...
Frontiers in neuroendocrinology, 1992
All the classes of hormonal steroids physiologically produced in the body (androgens, estrogens, ... more All the classes of hormonal steroids physiologically produced in the body (androgens, estrogens, progestagens, and corticosteroids) are able to exert important effects on the brain, but the mechanisms of their actions are not always well understood. Steroids may interact with intracellular receptors to activate the genome, but some of their effects are probably extragenomic and involve interactions with cellular membranes. Moreover, not all the steroids act always in their native molecular form; a large group of them must actually be transformed into "active" metabolites. This may occur at the level of their respective target structures. For example, androgens are metabolized in the brain into estrogens and into 5 alpha-reduced androgens, like 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone; DHT) and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol). Progesterone, and possibly corticosteroids, may also be transformed into their corresponding 5 alpha-reduced me...
Endocrine regulations, 1992
The formation of the 5 alpha-reduced metabolites of testosterone, 5 alpha-androstan-17 beta-ol-3-... more The formation of the 5 alpha-reduced metabolites of testosterone, 5 alpha-androstan-17 beta-ol-3-one (dihydroxytestosterone, DHT) and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol) was evaluated in sciatic nerve fragments and homogenates and in the myelin purified from the sciatic nerve of adult (60-90-day-old) male rats. The effects of aging on the metabolism of testosterone in the sciatic nerve was also evaluated using 20-month-old animals. In the sciatic nerve, tissue homogenization and myelin purification are associated with a marked decrease in the 5 alpha-reductase activity; these data do not appear to be consistent with a possible association of the enzyme with myelin membranes, as it occurs in the CNS. However, the results may be subject to other interpretations which are presented in the discussion. The formation of 3 alpha-diol is higher in sciatic nerve fragments than in homogenates or in the purified myelin. This occurs when testosterone is used as the substrate....
6° Congresso Nazionale dell’Italian Society Space Biomedicine Biotechnology, 2012
Clinical Cancer Drugs, 2016
Background: The importance of epigenetics in cancer is well known. Since many epigenetic mechanis... more Background: The importance of epigenetics in cancer is well known. Since many epigenetic mechanisms are involved in cancer progression, they may represent a target for a new pharmacological approach. Prostate cancer is the most common malignancy in men. After failure of the androgen deprivation therapy, the recurrent disease is termed castration- resistant cancer (CRPC). Since CRPC remains an incurable disease, new studies are focusing on the mechanisms critical for CRPC development, to identify new pharmacological targets. Methods: A MEDLINE research related to CRPC and epigenome has been carried out. Results: CRPC is probably due to several genetic and epigenetic mechanisms involved in AR activation, even in the presence of low androgen levels. Increasing evidence suggests that an aberrant DNA methylation may promote CRPC progression, augmenting genomic instability. Deregulated miRNAs are involved in initiation, progression, and metastatization of prostate cancers. MiRNAs may act like oncogenes (oncomirs) which can promote cancer progression, or tumor suppressors (anti-oncomirs) which inhibit CRPC progression. miRNA replacement therapy represents the most promising anticancer strategy, however only MRX34 (a doublestranded RNA mimic of the anti-oncomir, miR-34) has reached phase I clinical trial. Also, the deregulation of long non coding RNAs (lncRNAs) has been involved in CRPC development and lncRNAs may gain diagnostic/ therapeutic relevance. Recently research was focused on the chromatin reader proteins containing bromodomain and extraterminal domain (BET family). Since BET inhibitors act downstream of AR, these compounds might be effective in a condition of mediated AR resistance to androgen deprivation. Conclusions: The recent finding about CRPC epigenome might provide several emerging treatment strategies to counteract efficiently the tumor progression
It is known that Aromatase (Aro), the enzyme which metabolizes androgens into estrogens, and 5alp... more It is known that Aromatase (Aro), the enzyme which metabolizes androgens into estrogens, and 5alpha-reductase type2 (5\u3b1-R2), which specifically forms DHT, increase their expression and activity in late gestation. We have evaluated, by semiquantitative RT-PCR, the existence of a possible dimorphism of these enzymes during development (from gestational day 16 to postnatal day 5) and some of the factors controlling their expression; in particular, the formation of brain speific Aro transcript (containing Exon If) in comparison with the total expression of this enzyme (including variants differing in the 5'-untranslated regions). It has been observed that Aro has two male-specific peaks of expression, before and after birth and only exon If is used in males, while transcripts other than the brain-specific one are also present in females postnatally. Also the 5alpha-R2 expression is higher in males than in females, particularly just after birth. We can conclude that the sexual differentiation of rodent brain probably involves the activation of both Aro and 5alpha-R2 in a sex- and time-specific pattern
Journal of Steroid Biochemistry, 1987
It is known that the metabolism of testosterone in the brain and in the anterior pituitary is dif... more It is known that the metabolism of testosterone in the brain and in the anterior pituitary is different in mammalian and in photoperiodic avian species. In many mammalian species, testosterone is mainly metabolized to 5-alpha-reduced compounds (e.g. 17-beta-hydroxy-5-alpha-androstan- 3-one, 5 alpha-DHT and 3-alpha,17-beta-dihydroxy-5-alpha-androstane, 5-alpha,3-alpha-diol) and, to a smaller extent, to 4-androstene-3,17-dione (androstenedione), while in birds, androstenedione is the main testosterone metabolite and the conversion to the 5-alpha-reduced compounds is quantitatively negligible. In avian species, testosterone is also converted to 5-beta-reduced steroids (mainly 17-beta-hydroxy-5-beta-androstan-3-one, 5-beta-DHT and 3-alpha,17-beta-dihydroxy-5-beta-androstane, 5-beta,3-alpha-diol), and there is also evidence that in these species testosterone metabolism in the central structures may be influenced by the photoperiod. Since the hamster is a mammal whose reproductive cycle is controlled by day length, it has been analyzed whether: (a) the central structures of the hamster (cerebral cortex, hypothalamus and anterior pituitary) metabolize testosterone in vitro following a mammalian (5-alpha-reduced derivatives) or an avian (androstenedione and 5-beta-reduced compounds) pattern; and (b) the metabolism of testosterone in the same structures may be modified by the exposure to different photoperiods (LD 14:10 or LD 8:16). The present data indicate that no one of the hamster structures examined produces the 5-beta-reduced derivatives. Moreover, the formation of the 5 alpha-DHT is quantitatively low, and is not affected by the photoperiod. In contrast, androstenedione is formed in quite high yields and the exposure of the animals to 60 days of short photostimulation increases the formation of this steroid in the pituitary gland, but not in the brain structures. From these data, it appears that the central structures of the hamster metabolize testosterone with a pattern which is intermediate between that of birds and mammals.
Frontiers in Cell and Developmental Biology, 2015
Epigenetics represents the way by which the environment is able to program the genome; there are ... more Epigenetics represents the way by which the environment is able to program the genome; there are three main levels of epigenetic control on genome: DNA methylation, post-translational histone modification and microRNA expression. The term Epigenetics has been widened by NIH to include "both heritable changes in gene activity and expression but also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable." These changes might be produced mostly by the early life environment and might affect health influencing the susceptibility to develop diseases, from cancer to mental disorder, during the entire life span. The most studied environmental influences acting on epigenome are diet, infections, wasting, child care, smoking and environmental pollutants, in particular endocrine disrupters (EDs). These are environmental xenobiotics able to interfere with the normal development of the male and female reproductive systems of wildlife, of experimental animals and possibly of humans, disrupting the normal reproductive functions. Data from literature indicate that EDs can act at different levels of epigenetic control, in some cases transgenerationally, in particular when the exposure to these compounds occurs during the prenatal and earliest period of life. Some of the best characterized EDs will be considered in this review. Among the EDs, vinclozolin (VZ), and methoxychlor (MXC) promote epigenetic transgenerational effects. Polychlorinated biphenils (PCBs), the most widespread environmental EDs, affect histone post-translational modifications in a dimorphic way, possibly as the result of an alteration of gene expression of the enzymes involved in histone modification, as the demethylase Jarid1b, an enzyme also involved in regulating the interaction of androgens with their receptor.
Journal of endocrinological investigation, 2005
Effects of primary hypothyroidism (HYPO) on the male gonadal axis are controversial, with only sc... more Effects of primary hypothyroidism (HYPO) on the male gonadal axis are controversial, with only scanty data on the gonadotroph cell response and no information on GnRH tuberoinfundibular neurons, even in animal models. HYPO has been reported to variably induce hypogonadotropic hypogonadism, a hypergonadotropic state, or to have no effects on basal levels of pituitary gonadotropins, both in adult male rats and humans. Similarly, the exogenous administration of GnRH to HYPO rats and humans may increase or decrease gonadotropin secretion. Since inhibitory effects of HYPO on the GnRH-gonadotropin axis are reversed by replacement with L-T4, it has been suggested that thyroid hormone (TH) may regulate tuberoinfundibular GnRH and pituitary gonadotropin biosynthesis and/or secretion. To shed light on this hypothesis, we conducted immunocytochemical studies on the distribution and immunostaining characteristics of hypophysiotropic GnRH neurons, LH, PRL and vasoactive intestinal polypeptide (V...
Frontiers in neuroendocrinology, 1992
All the classes of hormonal steroids physiologically produced in the body (androgens, estrogens, ... more All the classes of hormonal steroids physiologically produced in the body (androgens, estrogens, progestagens, and corticosteroids) are able to exert important effects on the brain, but the mechanisms of their actions are not always well understood. Steroids may interact with intracellular receptors to activate the genome, but some of their effects are probably extragenomic and involve interactions with cellular membranes. Moreover, not all the steroids act always in their native molecular form; a large group of them must actually be transformed into "active" metabolites. This may occur at the level of their respective target structures. For example, androgens are metabolized in the brain into estrogens and into 5 alpha-reduced androgens, like 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone; DHT) and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol). Progesterone, and possibly corticosteroids, may also be transformed into their corresponding 5 alpha-reduced me...
Endocrine regulations, 1992
The formation of the 5 alpha-reduced metabolites of testosterone, 5 alpha-androstan-17 beta-ol-3-... more The formation of the 5 alpha-reduced metabolites of testosterone, 5 alpha-androstan-17 beta-ol-3-one (dihydroxytestosterone, DHT) and 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol) was evaluated in sciatic nerve fragments and homogenates and in the myelin purified from the sciatic nerve of adult (60-90-day-old) male rats. The effects of aging on the metabolism of testosterone in the sciatic nerve was also evaluated using 20-month-old animals. In the sciatic nerve, tissue homogenization and myelin purification are associated with a marked decrease in the 5 alpha-reductase activity; these data do not appear to be consistent with a possible association of the enzyme with myelin membranes, as it occurs in the CNS. However, the results may be subject to other interpretations which are presented in the discussion. The formation of 3 alpha-diol is higher in sciatic nerve fragments than in homogenates or in the purified myelin. This occurs when testosterone is used as the substrate....