Gabriella Nicolini | Università degli Studi di Milano-Bicocca (original) (raw)

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Papers by Gabriella Nicolini

Italian journal of anatomy and embryology, 2012

Journal of the Peripheral Nervous System, 2000

Frontiers in Bioscience, 2008

Cell cycle (Georgetown, Tex.), 2014

Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuro... more Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuropathy is likely to be a class side effect of these drugs, although its severity is largely variable, and it deserves to be further investigated, since the mechanisms of BTZ-induced peripheral neurotoxicity (BiPN) are still unknown. In our study, we investigated in vivo and in vitro possible pathogenic events relevant to BiPN using a well-established rat model, with particular reference to the extent of proteasome inhibition and the effects on α-tubulin polymerization in sciatic nerves and dorsal root ganglia specimens obtained from animals treated with chronic regimens at a dose of 0.2 mg/kg intravenously. The same assessments were also performed after a single injection. Moreover, these studies were replicated in vitro using embryonic DRG neurons exposed to 100 nM BTZ and adult DRG neurons exposed to 10-50 nM BTZ for 24 h and 48 h. A significant increase in the polymerized fraction of...

Anticancer research, 2014

Glioblastoma multiforme (GBM) is one of the deadliest cancers characterized by very limited sensi... more Glioblastoma multiforme (GBM) is one of the deadliest cancers characterized by very limited sensitivity to chemo- and/or radiotherapy. The presence of GBM stem-like cells in the tumor might be relevant for GBM treatment resistance. To provide a proof-of-concept of the efficacy of photon activation therapy (PAT) using monochromatic synchrotron radiation (SR), in killing GBM stem cells pre-treated with cisplatin. Irradiation was performed using a 1-8 Gy dose range and energies just above or below the platinum K-shell edge (78.39 keV) or with a conventional X-ray source. Cells were exposed to drug concentrations allowing 90% cell survival, mimicking the unfavourable tissue distribution generally achieved in GMB patients. a significant enhancement in cell lethality was observed using SR compared to conventional X-ray irradiation. PAT deserved to be further explored in in vivo models based on GBM stem-like cells.

Among the different families of intracellular molecules that can be modulated during cell damage ... more Among the different families of intracellular molecules that can be modulated during cell damage and repair, mitogen-activated protein kinases (MAPKs) are particularly interesting because they are involved in several intracellular pathways activated by injury and regeneration signals. Despite most of the studies have been performed in non-neurological models, recently a causal role for MAPKs has been postulated in central nervous system disorders. However, also in some peripheral neuropathies, MAPK changes can occur and these modifications might be relevant in the pathogenesis of the damage as well as during regeneration and repair. In this review, the current knowledge on the role of MAPKs in peripheral neuropathies will be discussed.

Neuroscience Letters, 1999

Phosphorylation of the mitogen-activated protein (MAP) kinases, extracellular signal-regulated ki... more Phosphorylation of the mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase 1 (ERK1) and extracellular signal-regulated kinase 2 (ERK2), induced by resveratrol, a natural antioxidant present in grapes and wine, has been studied in vitro on undifferentiated and differentiated (induction by retinoic acid) SH-SY5Y human neuroblastoma cells. In undifferentiated cells resveratrol 1 mM induced phosphorylation of ERK1 and ERK2, which was already evident at 2 min, peaked at 10 min and persisted at 30 min. A wide range (from 1 pM to 10 mM) of resveratrol concentrations were able to induce phosphorylation of ERK1 and ERK2, while higher concentrations (50-100 mM) inhibited MAP kinases phosphorylation. In retinoic acid (RA) differentiated cells resveratrol (1 mM) induced an evident increase in ERK1 and ERK2 phosphorylation. This study demonstrates that resveratrol, even at very low concentrations, may have a biological effect on neuron-like cells.

Journal of the Peripheral Nervous System, 2005

Quantification of cutaneous innervation in rat footpad is a useful tool to investigate sensory sm... more Quantification of cutaneous innervation in rat footpad is a useful tool to investigate sensory small-diameter nerve fibers, which are affected early in peripheral neuropathies. The aim of this work was to provide normative reference data on the density of intraepidermal nerve fibers (IENFs) and Langerhans cells in the hindpaw footpad of Sprague-Dawley and Wistar rats. We also evaluated the sensibility of IENF density by comparing neuropathologic findings with neurophysiologic examination and the presence of peripheral neuropathy in two well-characterized animal models of neuropathy. IENF density was quantified in 22 Sprague-Dawley rats and 13 Wistar rats and compared with 19 age-matched Sprague-Dawley rats with streptozotocin-induced diabetic neuropathy and 30 age-matched Wistar rats with cisplatin-or paclitaxel-induced neuropathy. Antidromic tail sensory nerve conduction velocity (SNCV) was assessed in all animals. IENF and Langerhans cell densities were constant in healthy Sprague-Dawley rats at any age, and they were similar to those observed in healthy Wistar rats. In neuropathic rats, both SNCV and IENF density were significantly reduced with respect to controls. Quantification of IENF density was significantly correlated with changes in conduction velocity. Diabetic neuropathy rats alone showed a significantly higher density of Langerhans cells compared with controls. Our study demonstrated that IENF density quantification correlates with SNCV changes and suggests that this might represent a useful outcome measurement in experimental neuropathies.

Journal of Neuroscience Research, 2010

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a side effect limiting cisplatin (CDDP) a... more Chemotherapy-induced peripheral neurotoxicity (CIPN) is a side effect limiting cisplatin (CDDP) and docetaxel (DOCE) treatment. Erythropoietin (EPO) is a hematopoietic growth factor also displaying neurotrophic properties. Evidence suggests that EPO's neuroprotective action may rely on PI3K/AKT pathway activation; however, data regarding the EPO neuroprotective mechanism are still limited. This study evaluated the effect of EPO on organotypic cultures of rat dorsal root ganglia (DRG) and in primary cultures of DRG-dissociated sensory neurons exposed to CDDP- and DOCE-induced neurotoxicity, aiming to investigate EPO's neuroprotective mechanism. Subsequently, the levels of AKT expression and activation were analyzed by Western blot in neurons exposed to CDDP or DOCE; AKT's role was further evaluated by using a chemical inhibitor of AKT activation, wortmannin. In these models EPO, was protective against both CDDP- and DOCE-induced cell death and against CDDP-induced neurite elongation reduction. A modulation of AKT activation was observed in CDDP-treated neurons, and the presence of wortmannin prevented EPO's neuroprotective action against CDDP toxicity but did not have any effect on EPO's protection against DOCE-induced toxicity, thus ruling out the PI3K-AKT pathway as the mechanism of EPO's effect in neuronal death prevention after DOCE exposure. Our results confirm in vitro the effectiveness of EPO as a neuroprotectant against both CDDP- and DOCE-induced neurotoxicity. In addition, a role of PI3K/AKT in EPO's protection against CDDP, but not against DOCE, neurotoxicity was shown, suggesting that alternative pathways could be involved in EPO's neuroprotective activity.

Journal of Biological Chemistry, 1996

Expression of epidermal growth factor receptor (EGF-R) antisense RNA results in a drastic reducti... more Expression of epidermal growth factor receptor (EGF-R) antisense RNA results in a drastic reduction of EGF-R levels in the human carcinoma KB cell line and induces a reversion of their transformed phenotype (Moroni, M. C., Willingham, M. C., and Beguinot, L. (1992) J. Biol. Chem. 267, 2714-2722). We used parental and EGF-R antisense KB clones as a genetic system to study, in the same cell line, the role of transforming growth factor alpha (TGF-alpha) in the establishment and maintenance of the transformed phenotype. KB cells produce TGF-alpha mRNA, and their conditioned medium is able to sustain growth of antisense cells, mimicking the effect of exogenous EGF or TGF-alpha. In antisense cells there is a marked reduction of TGF-alpha mRNA steady-state levels. In addition, the decrease in TGF-alpha parallels the levels of residual EGF-R in the various antisense clones, indicating a direct correlation between receptors and growth factor levels. The addition of exogenous TGF-alpha (10 ng/ml) to antisense clones induces TGF-alpha levels. The half-life of TGF-alpha mRNA is 40-60 min in antisense cells and more than 8 h in parental KB cells, as determined by actinomycin D decay curves. This result indicates a predominant regulation of TGF-alpha mRNA at the post-transcriptional level. Nuclear run-on experiments show that there is only a marginal effect at the transcriptional level. We conclude that the autocrine loop responsible for the transformed phenotype of the human carcinoma KB cell line is dependent on both elevated levels of EGF-R and the presence of TGF-alpha. In addition, TGF-alpha is able to induce its own mRNA via a signal due to activation of the EGF-R acting predominantly at the post-transcriptional level.

European Journal of Cancer, 2005

The experimentally induced neurotoxic effects of paclitaxel and docetaxel have never been compare... more The experimentally induced neurotoxic effects of paclitaxel and docetaxel have never been compared, since no animal models of docetaxel peripheral neurotoxicity have yet been reported. In this experiment, we examined the effect of the chronic administration of these two taxanes in the Wistar rat using neurophysiological, neuropathological and morphometrical methods.

Background: microRNAs are short RNAs that regulate gene expression in various processes, includin... more Background: microRNAs are short RNAs that regulate gene expression in various processes, including immune response. Altered immune response is a pivotal event in the pathogenesis of celiac disease (CD), and miRNA could have a role in modulating both innate and adaptive response to gluten in celiac patients,

Italian journal of anatomy and embryology, 2012

Journal of the Peripheral Nervous System, 2000

Frontiers in Bioscience, 2008

Cell cycle (Georgetown, Tex.), 2014

Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuro... more Bortezomib (BTZ) is the first proteasome inhibitor entered in clinical practice. Peripheral neuropathy is likely to be a class side effect of these drugs, although its severity is largely variable, and it deserves to be further investigated, since the mechanisms of BTZ-induced peripheral neurotoxicity (BiPN) are still unknown. In our study, we investigated in vivo and in vitro possible pathogenic events relevant to BiPN using a well-established rat model, with particular reference to the extent of proteasome inhibition and the effects on α-tubulin polymerization in sciatic nerves and dorsal root ganglia specimens obtained from animals treated with chronic regimens at a dose of 0.2 mg/kg intravenously. The same assessments were also performed after a single injection. Moreover, these studies were replicated in vitro using embryonic DRG neurons exposed to 100 nM BTZ and adult DRG neurons exposed to 10-50 nM BTZ for 24 h and 48 h. A significant increase in the polymerized fraction of...

Anticancer research, 2014

Glioblastoma multiforme (GBM) is one of the deadliest cancers characterized by very limited sensi... more Glioblastoma multiforme (GBM) is one of the deadliest cancers characterized by very limited sensitivity to chemo- and/or radiotherapy. The presence of GBM stem-like cells in the tumor might be relevant for GBM treatment resistance. To provide a proof-of-concept of the efficacy of photon activation therapy (PAT) using monochromatic synchrotron radiation (SR), in killing GBM stem cells pre-treated with cisplatin. Irradiation was performed using a 1-8 Gy dose range and energies just above or below the platinum K-shell edge (78.39 keV) or with a conventional X-ray source. Cells were exposed to drug concentrations allowing 90% cell survival, mimicking the unfavourable tissue distribution generally achieved in GMB patients. a significant enhancement in cell lethality was observed using SR compared to conventional X-ray irradiation. PAT deserved to be further explored in in vivo models based on GBM stem-like cells.

Among the different families of intracellular molecules that can be modulated during cell damage ... more Among the different families of intracellular molecules that can be modulated during cell damage and repair, mitogen-activated protein kinases (MAPKs) are particularly interesting because they are involved in several intracellular pathways activated by injury and regeneration signals. Despite most of the studies have been performed in non-neurological models, recently a causal role for MAPKs has been postulated in central nervous system disorders. However, also in some peripheral neuropathies, MAPK changes can occur and these modifications might be relevant in the pathogenesis of the damage as well as during regeneration and repair. In this review, the current knowledge on the role of MAPKs in peripheral neuropathies will be discussed.

Neuroscience Letters, 1999

Phosphorylation of the mitogen-activated protein (MAP) kinases, extracellular signal-regulated ki... more Phosphorylation of the mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase 1 (ERK1) and extracellular signal-regulated kinase 2 (ERK2), induced by resveratrol, a natural antioxidant present in grapes and wine, has been studied in vitro on undifferentiated and differentiated (induction by retinoic acid) SH-SY5Y human neuroblastoma cells. In undifferentiated cells resveratrol 1 mM induced phosphorylation of ERK1 and ERK2, which was already evident at 2 min, peaked at 10 min and persisted at 30 min. A wide range (from 1 pM to 10 mM) of resveratrol concentrations were able to induce phosphorylation of ERK1 and ERK2, while higher concentrations (50-100 mM) inhibited MAP kinases phosphorylation. In retinoic acid (RA) differentiated cells resveratrol (1 mM) induced an evident increase in ERK1 and ERK2 phosphorylation. This study demonstrates that resveratrol, even at very low concentrations, may have a biological effect on neuron-like cells.

Journal of the Peripheral Nervous System, 2005

Quantification of cutaneous innervation in rat footpad is a useful tool to investigate sensory sm... more Quantification of cutaneous innervation in rat footpad is a useful tool to investigate sensory small-diameter nerve fibers, which are affected early in peripheral neuropathies. The aim of this work was to provide normative reference data on the density of intraepidermal nerve fibers (IENFs) and Langerhans cells in the hindpaw footpad of Sprague-Dawley and Wistar rats. We also evaluated the sensibility of IENF density by comparing neuropathologic findings with neurophysiologic examination and the presence of peripheral neuropathy in two well-characterized animal models of neuropathy. IENF density was quantified in 22 Sprague-Dawley rats and 13 Wistar rats and compared with 19 age-matched Sprague-Dawley rats with streptozotocin-induced diabetic neuropathy and 30 age-matched Wistar rats with cisplatin-or paclitaxel-induced neuropathy. Antidromic tail sensory nerve conduction velocity (SNCV) was assessed in all animals. IENF and Langerhans cell densities were constant in healthy Sprague-Dawley rats at any age, and they were similar to those observed in healthy Wistar rats. In neuropathic rats, both SNCV and IENF density were significantly reduced with respect to controls. Quantification of IENF density was significantly correlated with changes in conduction velocity. Diabetic neuropathy rats alone showed a significantly higher density of Langerhans cells compared with controls. Our study demonstrated that IENF density quantification correlates with SNCV changes and suggests that this might represent a useful outcome measurement in experimental neuropathies.

Journal of Neuroscience Research, 2010

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a side effect limiting cisplatin (CDDP) a... more Chemotherapy-induced peripheral neurotoxicity (CIPN) is a side effect limiting cisplatin (CDDP) and docetaxel (DOCE) treatment. Erythropoietin (EPO) is a hematopoietic growth factor also displaying neurotrophic properties. Evidence suggests that EPO's neuroprotective action may rely on PI3K/AKT pathway activation; however, data regarding the EPO neuroprotective mechanism are still limited. This study evaluated the effect of EPO on organotypic cultures of rat dorsal root ganglia (DRG) and in primary cultures of DRG-dissociated sensory neurons exposed to CDDP- and DOCE-induced neurotoxicity, aiming to investigate EPO's neuroprotective mechanism. Subsequently, the levels of AKT expression and activation were analyzed by Western blot in neurons exposed to CDDP or DOCE; AKT's role was further evaluated by using a chemical inhibitor of AKT activation, wortmannin. In these models EPO, was protective against both CDDP- and DOCE-induced cell death and against CDDP-induced neurite elongation reduction. A modulation of AKT activation was observed in CDDP-treated neurons, and the presence of wortmannin prevented EPO's neuroprotective action against CDDP toxicity but did not have any effect on EPO's protection against DOCE-induced toxicity, thus ruling out the PI3K-AKT pathway as the mechanism of EPO's effect in neuronal death prevention after DOCE exposure. Our results confirm in vitro the effectiveness of EPO as a neuroprotectant against both CDDP- and DOCE-induced neurotoxicity. In addition, a role of PI3K/AKT in EPO's protection against CDDP, but not against DOCE, neurotoxicity was shown, suggesting that alternative pathways could be involved in EPO's neuroprotective activity.

Journal of Biological Chemistry, 1996

Expression of epidermal growth factor receptor (EGF-R) antisense RNA results in a drastic reducti... more Expression of epidermal growth factor receptor (EGF-R) antisense RNA results in a drastic reduction of EGF-R levels in the human carcinoma KB cell line and induces a reversion of their transformed phenotype (Moroni, M. C., Willingham, M. C., and Beguinot, L. (1992) J. Biol. Chem. 267, 2714-2722). We used parental and EGF-R antisense KB clones as a genetic system to study, in the same cell line, the role of transforming growth factor alpha (TGF-alpha) in the establishment and maintenance of the transformed phenotype. KB cells produce TGF-alpha mRNA, and their conditioned medium is able to sustain growth of antisense cells, mimicking the effect of exogenous EGF or TGF-alpha. In antisense cells there is a marked reduction of TGF-alpha mRNA steady-state levels. In addition, the decrease in TGF-alpha parallels the levels of residual EGF-R in the various antisense clones, indicating a direct correlation between receptors and growth factor levels. The addition of exogenous TGF-alpha (10 ng/ml) to antisense clones induces TGF-alpha levels. The half-life of TGF-alpha mRNA is 40-60 min in antisense cells and more than 8 h in parental KB cells, as determined by actinomycin D decay curves. This result indicates a predominant regulation of TGF-alpha mRNA at the post-transcriptional level. Nuclear run-on experiments show that there is only a marginal effect at the transcriptional level. We conclude that the autocrine loop responsible for the transformed phenotype of the human carcinoma KB cell line is dependent on both elevated levels of EGF-R and the presence of TGF-alpha. In addition, TGF-alpha is able to induce its own mRNA via a signal due to activation of the EGF-R acting predominantly at the post-transcriptional level.

European Journal of Cancer, 2005

The experimentally induced neurotoxic effects of paclitaxel and docetaxel have never been compare... more The experimentally induced neurotoxic effects of paclitaxel and docetaxel have never been compared, since no animal models of docetaxel peripheral neurotoxicity have yet been reported. In this experiment, we examined the effect of the chronic administration of these two taxanes in the Wistar rat using neurophysiological, neuropathological and morphometrical methods.

Background: microRNAs are short RNAs that regulate gene expression in various processes, includin... more Background: microRNAs are short RNAs that regulate gene expression in various processes, including immune response. Altered immune response is a pivotal event in the pathogenesis of celiac disease (CD), and miRNA could have a role in modulating both innate and adaptive response to gluten in celiac patients,