Papers by Valentina Pallottini
American Journal of Physiology-cell Physiology, Nov 1, 2009
Estradiol (E 2) mediates a wide variety of complex biological processes determining the growth an... more Estradiol (E 2) mediates a wide variety of complex biological processes determining the growth and development of reproductive tract as well as nonreproductive tissues of male and female individuals. While E 2 effects on the reproductive system, bone, and cardiovascular system are quite well established, less is known about how it affects the physiology of other tissues. Skeletal muscle is a tissue that is expected to be E2 responsive since both isoforms of estrogen receptor (ER-␣ and ER-) are expressed. Significant sex-related differences have been described in skeletal muscle, although the role played by E2 and the mechanisms underlying it remain to be determined. Here, we demonstrate that E2 increases the glucose transporter type 4 translocation at membranes as well as the expression of well-known differentiation markers of myogenesis (i.e., myogenin and myosin heavy chain) in rat myoblast cells (L6). These E2-induced effects require rapid extranuclear signals and the presence of ER-␣, whereas no contribution of IGF-I receptor has been observed. In particular, ER-␣-dependent Akt activation participates in regulating the first step of myogenic differentiation. Moreover, both receptors mediate the E2-induced activation of p38, which, in turn, affects the expression of myogenin and myosin heavy chain. All together, these data indicate that E2 should be included in the list of skeletal muscle trophic factors.
Cellular Signalling, Dec 1, 2015
Estrogen Receptor α L429 and A430 Regulate 17β-estradiol-induced cell proliferation via CREB1.
Molecular and Cellular Endocrinology, Dec 1, 2021
Over the last decades, a great body of evidence has defined a novel view of the cellular mechanis... more Over the last decades, a great body of evidence has defined a novel view of the cellular mechanism of action of the steroid hormone 17β-estradiol (E2) through its estrogen receptors (i.e., ERα and ERβ). It is now clear that the E2-activated ERs work both as transcription factors and extra-nuclear plasma membrane-localized receptors. The activation of a plethora of signal transduction cascades follows the E2-dependent engagement of plasma membrane-localized ERs and is required for the coordination of gene expression, which ultimately controls the occurrence of the pleiotropic effects of E2. The definition of the molecular mechanisms by which the ERs locate at the cell surface (i.e., palmitoylation and protein association) determined the quest for understanding the specificity of the extra-nuclear E2 signaling. The use of mice models lacking the plasma membrane ERα localization unveiled that the extra-nuclear E2 signaling is operational in vivo but tissue-specific. However, the underlying molecular details for such ERs signaling diversity in the perspective of the E2 physiological functions in the different cellular contexts are still not understood. Therefore, to gain insights into the tissue specificity of the extra-nuclear E2 signaling to physiological functions, here we reviewed the known ERs extra-nuclear interactors and tried to extrapolate from available databases the ERα and ERβ extra-nuclear interactomes. Based on literature data, it is possible to conclude that by specifically binding to extra-nuclear localized proteins in different sub-cellular compartments, the ERs fine-tune their molecular activities. Moreover, we report that the context-dependent diversity of the ERs-mediated extra-nuclear E2 actions can be ascribed to the great flexibility of the physical structures of ERs and the spatial-temporal organization of the logistics of the cells (i.e., the endocytic compartments). Finally, we provide lists of proteins belonging to the potential ERα and ERβ extra-nuclear interactomes and propose that the systematic experimental definition of the ERs extra-nuclear interactomes in different tissues represents the next step for the research in the ERs field. Such characterization will be fundamental for the identification of novel druggable targets for the innovative treatment of ERs-related diseases.
Translational Psychiatry, Sep 27, 2016
Autism spectrum disorders (ASD) are characterized by altered sociability, compromised communicati... more Autism spectrum disorders (ASD) are characterized by altered sociability, compromised communication and stereotyped/repetitive behaviors, for which no specific treatments are currently available. Prenatal exposure to valproic acid (VPA) is a known, although still underestimated, environmental risk factor for ASD. Altered endocannabinoid activity has been observed in autistic patients, and endocannabinoids are known to modulate behavioral traits that are typically affected in ASD. On this basis, we tested the hypothesis that changes in the endocannabinoid tone contribute to the altered phenotype induced by prenatal VPA exposure in rats, with focus on behavioral features that resemble the core and associated symptoms of ASD. In the course of development, VPA-exposed rats showed early deficits in social communication and discrimination, compromised sociability and social play behavior, stereotypies and increased anxiety, thus providing preclinical proof of the long-lasting deleterious effects induced by prenatal VPA exposure. At the neurochemical level, VPA-exposed rats displayed altered phosphorylation of CB1 cannabinoid receptors in different brain areas, associated with changes in anandamide metabolism from infancy to adulthood. Interestingly, enhancing anandamide signaling through inhibition of its degradation rescued the behavioral deficits displayed by VPA-exposed rats at infancy, adolescence and adulthood. This study therefore shows that abnormalities in anandamide activity may underlie the deleterious impact of environmental risk factors on ASD-relevant behaviors and that the endocannabinoid system may represent a therapeutic target for the core and associated symptoms displayed by autistic patients.
International Journal of Molecular Sciences
Induced pluripotent stem cells (iPSCs) have been established as a reliable in vitro disease model... more Induced pluripotent stem cells (iPSCs) have been established as a reliable in vitro disease model system and represent a particularly informative tool when animal models are not available or do not recapitulate the human pathophenotype. The recognized limit in using this technology is linked to some degree of variability in the behavior of the individual patient-derived clones. The development of CRISPR/Cas9-based gene editing solves this drawback by obtaining isogenic iPSCs in which the genetic lesion is corrected, allowing a straightforward comparison with the parental patient-derived iPSC lines. Here, we report the generation of a footprint-free isogenic cell line of patient-derived TBCD-mutated iPSCs edited using the CRISPR/Cas9 and piggyBac technologies. The corrected iPSC line had no genetic footprint after the removal of the selection cassette and maintained its “stemness”. The correction of the disease-causing TBCD missense substitution restored proper protein levels of the ...
The detrimental impact of fructose, a widely used sweetener in industrial foods, was previously e... more The detrimental impact of fructose, a widely used sweetener in industrial foods, was previously evidenced on various brain regions. Although adolescents are among the highest consumers of sweet foods, whether brain alterations induced by the sugar intake during this age persist until young adulthood or are rescued returning to a healthy diet remains largely unexplored. To shed light on this issue, adolescent rats were fed with a fructose-rich or control diet for 3 weeks. At the end of the treatment, fructose-fed rats underwent a control diet for a further 3 weeks until young adulthood phase, and compared with animals that received from the beginning the healthy control diet. We focused on the consequences induced by the sugar on the main neurotrophins and neurotransmitters in the frontal cortex, as its maturation continues until late adolescence, thus being the last brain region to achieve a full maturity. We here outline that fructose intake induces inflammation and oxidative stres...
Nutrients, 2021
Background: A major problem of aging is the disruption of metabolic homeostasis. This is particul... more Background: A major problem of aging is the disruption of metabolic homeostasis. This is particularly relevant in the brain where it provokes neurodegeneration. Caloric restriction is a physiologic intervention known to delay the deleterious consequences of aging in several species ranging from yeast to mammals. To date, most studies on experimental models have started this dietary intervention from weaning, which is very difficult to be translated to human beings. Here, we study the effects of a more realistic dietary regimen in rats, starting at an advanced age and lasting for six months. Methods: we analyzed in the cortex and hippocampus, the proteins involved in the energetic balance of the cells, cholesterol metabolism, oxidative stress response, inflammation, synaptic impairment, and brain trophism. Results: our results suggest that caloric restriction in late life can revert only some age-related changes studied here.
We present here a brief description of the path that cholesterol covers from its intestinal absor... more We present here a brief description of the path that cholesterol covers from its intestinal absorption to its effect exerted on some enzyme regulation. Some mechanisms underlying hypercholesterolemia onset and, in particular, the role and the regulation of 3hydroxy 3-methylglutaryl Coenzyme A reductase (HMGR) during adult life and during aging, have been described. In addition some pharmacological interventions to control proper HMGR regulation and, in turn, cholesterol homeostasis maintenance will be introduced.
The mevalonate (MVA) pathway is an essential metabolic pathway that leads to the production of mo... more The mevalonate (MVA) pathway is an essential metabolic pathway that leads to the production of molecules important in several physiological processes and play pivotal roles in the brain. An imbalance of this pathway in CNS is accompanied by the onset of several neuropathological descriptions. Despite these observations, the physiological importance of this metabolic process in the brain has remained unclear. My aim was to study the presence and the regulation of the proteins involved in the MVA pathway in different rat brain areas in a sex- and age-dependent manner, to analyze the impact of the key enzymes on neuronal development and on rat behavior, and to explore whether the MVA pathway is affected in a neurodevelopmental disease such as autism. My results demonstrate that this metabolic process is expressed and modulated in a highly region-dependent manner and that age and sex induce physiological differences. Notably, it impact on behavior and neuronal development suggesting tha...
Nutrients, 2021
Bisphenol A (BPA) is an organic chemical compound widely used for manufacturing plastics. BPA exp... more Bisphenol A (BPA) is an organic chemical compound widely used for manufacturing plastics. BPA exposure originates principally from the diet, but it can also originate from dermal contact. In over 90% of individuals, including pregnant women, BPA is detectable in several body fluids. The effects of this exposure on the fetus are under active investigation in several research laboratories. The aim of our work was to study the impact of prenatal exposure to BPA in the liver of rat fetuses from a sex-dependent point of view. We particularly investigated the effects of prenatal BPA exposure on hepatic lipids because of their crucial role, not only for the liver, but also for the whole-body functions. Our results demonstrate that the liver of rat fetuses, in utero exposed to a very low dose of BPA (2.5 µg/kg/day), displays significant modulations with regard to proteins involved in cholesterol and fatty acid biosynthesis and trafficking. Moreover, an impact on inflammatory process has bee...
Frontiers in Endocrinology, 2019
Thyroid hormones T3 and T4 (thyroxine) control a wide variety of effects related to development, ... more Thyroid hormones T3 and T4 (thyroxine) control a wide variety of effects related to development, differentiation, growth and metabolism, through their interaction with nuclear receptors. But thyroid hormones also produce non-genomic effects that typically start at the plasma membrane and are mediated mainly by integrin αvβ3, although other receptors such as TRα and TRβ are also able to elicit non-genomic responses. In the liver, the effects of thyroid hormones appear to be particularly important. The liver is able to regenerate, but it is subject to pathologies that may lead to cancer, such as fibrosis, cirrhosis, and non-alcoholic fatty liver disease. In addition, cancer cells undergo a reprogramming of their metabolism, resulting in drastic changes such as aerobic glycolysis instead of oxidative phosphorylation. As a consequence, the pyruvate kinase isoform M2, the rate-limiting enzyme of glycolysis, is dysregulated, and this is considered an important factor in tumorigenesis. Redox equilibrium is also important, in fact cancer cells give rise to the production of more reactive oxygen species (ROS) than normal cells. This increase may favor the survival and propagation of cancer cells. We evaluate the possible mechanisms involving the plasma membrane receptor integrin αvβ3 that may lead to cancer progression. Studying diseases that affect the liver and their experimental models may help to unravel the cellular pathways mediated by integrin αvβ3 that can lead to liver cancer. Inhibitors of integrin αvβ3 might represent a future therapeutic tool against liver cancer. We also include information on the possible role of exosomes in liver cancer, as well as on recent strategies such as organoids and spheroids, which may provide a new tool for research, drug discovery, and personalized medicine.
International Journal of Molecular Sciences, 2020
Although initially regarded as a passive system to store energy, lipids are now considered to pla... more Although initially regarded as a passive system to store energy, lipids are now considered to play crucial, structural and functional roles in almost all the biological processes involved in the regulation of physiological and pathological conditions [...]
Nutrients, 2020
Bisphenol A (BPA) is a synthetic compound widely used for the production of polycarbonate plastic... more Bisphenol A (BPA) is a synthetic compound widely used for the production of polycarbonate plasticware and epoxy resins. BPA exposure is widespread and more than 90% of individuals have detectable amounts of the molecule in their body fluids, which originates primarily from diet. Here, we investigated whether prenatal exposure to BPA affects the mevalonate (MVA) pathway in rat brain fetuses, and whether potential effects are sex-dependent. The MVA pathway is important for brain development and function. Our results demonstrate that the fetal brain, exposed in utero to a very low dose of BPA (2.5 µg/kg/day), displayed altered MVA pathway activation, increased protein prenylation, and a decreased level of pro-BDNF. Interestingly, the BPA-induced effects on estrogen receptor α were sex-dependent. In conclusion, this work demonstrates intergenerational effects of BPA on the brain at very low doses. Our results reveal new targets for BPA-induced interference and underline the impacts of B...
Current Neuropharmacology, 2017
Background:Statins represent a class of medications widely prescribed to efficiently treat dyslip... more Background:Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-βhydroxy 3β-methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essential in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statins are able to induce pleiotropic actions, and acquire increased interest as potential and novel modulators in brain processes, especially during pathological conditions. Objective: The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and pharmacodynamic properties of statins in the brain. In addition, effects of statin on brain diseases are discussed providing the most up-to-date information. Methods: Relevant scientific information was identified from PubMed database using the fo...
Journal of the American Society of Nephrology : JASN, Feb 19, 2016
Renal inflammation has a key role in the onset and progression of immune- and nonimmune-mediated ... more Renal inflammation has a key role in the onset and progression of immune- and nonimmune-mediated renal diseases. Therefore, the search for novel anti-inflammatory pharmacologic targets is of great interest in renal pathology. JQ1, a small molecule inhibitor of bromodomain and extraterminal (BET) proteins, was previously found to preserve renal function in experimental polycystic kidney disease. We report here that JQ1-induced BET inhibition modulated the in vitro expression of genes involved in several biologic processes, including inflammation and immune responses. Gene silencing of BRD4, an important BET protein, and chromatin immunoprecipitation assays showed that JQ1 alters the direct association of BRD4 with acetylated histone-packaged promoters and reduces the transcription of proinflammatory genes (IL-6, CCL-2, and CCL-5). In vivo, JQ1 abrogated experimental renal inflammation in murine models of unilateral ureteral obstruction, antimembrane basal GN, and infusion of Angioten...
Dose-Response, 2015
Bisphenol A (BPA) exposure has been associated with serious endocrine-disrupting effects in human... more Bisphenol A (BPA) exposure has been associated with serious endocrine-disrupting effects in humans and wildlife. Toxicological and epidemiological studies evidenced that BPA increases body mass index and disrupts normal cardiovascular physiology by interfering with endogenous hormones in rodents, nonhuman primates, and cell culture test systems. The BPA concentration derived from these experiments were used by government regulatory agencies to determine the safe exposure levels of BPA in humans. However, accumulating literature in vivo and in vitro indicate that at concentrations lower than that reported in toxicological studies, BPA could elicit a different endocrine-disrupting capacity. To further complicate this picture, BPA effects rely on several and diverse mechanisms that converge upon endocrine and reproductive systems. If all or just few of these mechanisms concur to the endocrine-disrupting potential of low doses of BPA is at present still unclear. Thus, taking into accoun...
Cellular Signalling, 2015
Estrogen Receptor α L429 and A430 Regulate 17β-estradiol-induced cell proliferation via CREB1.
Open Journal of Molecular and Integrative Physiology, 2013
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Papers by Valentina Pallottini