Angela Stefano - Academia.edu (original) (raw)
Papers by Angela Stefano
Endocrine-Related Cancer
Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedif... more Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial–mesenchymal transition. Here, we show that D2 is highly expressed in anaplastic compared to papillary thyroid cancer cell lines and that D2-derived T3 is required for ATC cell proliferation. D2 inhibition is associated with G1 growth arrest and induction of cell senescence, together with reduced cell migration and invasive potential. Finally, we found that mutated p5372R(R248W), frequently found in ATC, is able to induce D2 expression in transfected papillary thyroid cancer cells. Our result...
Endocrine-Related Cancer
The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) level... more The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) levels. The two TH-activating deiodinases (type 1 deiodinase and type 2 deiodinase (D2)) are normally expressed in follicular thyroid cells and contribute to overall TH production. During thyroid tumorigenesis, the deiodinase expression profile changes to customize intracellular TH levels to different requirements of cancer cells. Differentiated thyroid cancers overexpress the TH-inactivating type 3 deiodinase (D3), likely to reduce the TH signaling within the tumor. Strikingly, recent evidence suggests that during the late stage of thyroid tumorigenesis, D2 expression raises and this, together with a reduction in D3 expression levels, increases TH intracellular signaling in dedifferentiated thyroid cancers. These findings call into question the different functions of TH in the various stages of thyroid cancers.
Journal of Orthopedic Research and Therapy, 2021
Current Oncology, 2021
Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50... more Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50% of all thyroid cancer-related deaths. During the last two decades, the development of a multimodal personalized approach resulted in an increased survival. Here, we present an unusual case of a 54-year old woman with a paucicellular metastatic ATC, a rare variant of ATC, who was treated with a combination of surgery, radiation therapy and cytotoxic chemotherapy. More than two years later, when the disease was rapidly growing, a combination of lenvatinib and pembrolizumab induced a partial tumor response of lung metastasis that persisted over 18 months. Paucicellular ATC may initially show a less aggressive behavior compared to other histological ATC variants. However, over the time, its clinical course can rapidly progress like common ATC. The combination of lenvatinib and pembrolizumab was effective as a salvage therapy for a long period of time.
Metabolites, 2021
Skeletal muscle atrophy is a condition associated with various physiological and pathophysiologic... more Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin–proteasome. Thyroid hormone (TH) plays a key role in these conditions. Indeed, skeletal muscle is among the principal TH target tissue, where TH regulates proliferation, metabolism, differentiation, homeostasis, and growth. In physiological conditions, TH stimulates both protein synthesis and degradation, and an alteration in TH levels is often responsible for a specific myopathy. Intracellular TH concentrations are modulated in skeletal muscle by a family of enzymes named deiodinases; in particular, in musc...
Endocrinology, 2021
Hormones are key drivers of cancer development, and alteration of the intratumoral concentration ... more Hormones are key drivers of cancer development, and alteration of the intratumoral concentration of thyroid hormone (TH) is a common feature of many human neoplasias. Besides the systemic control of TH levels, the expression and activity of deiodinases constitute a major mechanism for the cell-autonomous, prereceptoral control of TH action. The action of deiodinases ensures tight control of TH availability at intracellular level in a time- and tissue-specific manner, and alterations in deiodinase expression are frequent in tumors. Research over the past decades has shown that in cancer cells, a complex and dynamic expression of deiodinases is orchestrated by a network of growth factors, oncogenic proteins, and miRNA. It has become increasingly evident that this fine regulation exposes cancer cells to a dynamic concentration of TH that is functional to stimulate or inhibit various cellular functions. This review summarizes recent advances in the identification of the complex interpla...
Nature Communications, 2020
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Proceedings of the International Conference on Health Informatics, 2011
Large amounts of images (SPECT, PET, scintigraphy) in the nuclear medicine field have been routin... more Large amounts of images (SPECT, PET, scintigraphy) in the nuclear medicine field have been routinely produced in the last decades. In this paper we propose an image management system that allows nuclear medicine physicians to share the acquired images and the associated metadata both locally (i.e. within the same medical institute) and globally with other nuclear medicine physicians located anywhere in the world by using GRID services for data (LFC) and metadata (AMGA) storage. The proposed system guarantees medical data protection by anonymization that removes most sensitive data for unauthorized users, and encryption, that guarantees data protection when it is stored at remote sites. Another important issue is that often nuclear medicine data is associated with other medical data (e.g. neurological data) for diagnosis and therapy follow-up. In order to correlate images with other clinical information, the common metadata are enriched by developing a controlled vocabulary, which integrates known standards such as FOAF, CCR and GeneOntology. All the metadata are stored in an RDF (Resource Description Framework) repository in order to make the system fully compatible with existing metadata storage systems following the semantic web's philosophy.
Cancers, 2020
Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissu... more Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissues, is expressed in cutaneous squamous cell carcinomas (SCCs) during late tumorigenesis, and its repression attenuates the invasiveness and metastatic spread of SCC. Although D2 plays multiple roles in cancer progression, nothing is known about the mechanisms regulating D2 in cancer. To address this issue, we investigated putative upstream regulators of D2 in keratinocyte carcinomas. We found that the expression of D2 in SCC cells is positively regulated by the NANOG transcription factor, whose expression, besides being causally linked to embryonic stemness, is associated with many human cancers. We also found that NANOG binds to the D2 promoter and enhances D2 transcription. Notably, blockage of D2 activity reduced NANOG-induced cell migration as well as the expression of key genes involved in epithelial–mesenchymal transition in SCC cells. In conclusion, our study reveals a link among ...
Thyroid, 2020
Thyroid hormones (THs) are key regulators of development, tissue differentiation and maintenance ... more Thyroid hormones (THs) are key regulators of development, tissue differentiation and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 deiodinase (D3), the TH inactivating enzyme. Here, we demonstrate that D3 is dynamically regulated during epidermal ontogenesis. To investigate the function of D3 in a post-developmental context, we used a mouse model of conditional epidermal-specific D3 depletion. Loss of D3 resulted in tissue hypoplasia and enhanced epidermal differentiation in a cell-autonomous manner. Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Furthermore, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were up-regulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular T3 levels. Notably, loss of D3 reduced the clearance of systemic TH in vivo, thereby demonstrating the critical requirement for epidermal D3 in the maintenance of TH homeostasis. In conclusion, our results show that the D3 enzyme is a key TH-signaling component in the skin thereby providing a striking example of a physiological context for deiodinase-mediated TH metabolism, as well as a rationale for therapeutic manipulation of deiodinases in patho-physiological contexts.
Nature Communications, 2019
Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report th... more Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses E-cadherin expression. Accordingly, in human SCC, elevated D2 (the T3-producing enzyme) correlates with tumor grade and is associated with an increased risk of postsurgical relapse and shorter disease-free survival. These data provide the first in vivo demonstration that TH and its activating enzyme, D2, play an effective role not only in the EMT but also in the entire neoplastic cascade starting from tumor formation up to metastatic transformation, and supports the concept that TH is an EMT promoter. Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH sig...
Redox Biology, 2019
Thyroid hormone (TH) is a key metabolic regulator that acts by coordinating short-and long-term e... more Thyroid hormone (TH) is a key metabolic regulator that acts by coordinating short-and long-term energy needs. Accordingly, significant metabolic changes are observed depending on thyroid status. Although it is established that hyperthyroidism augments basal energy consumption, thus resulting in an enhanced metabolic state, the net effects on cellular respiration and generation of reactive oxygen species (ROS) remain unclear. To elucidate the effects of augmented TH signal in muscle cells, we generated a doxycycline-inducible cell line in which the expression of the TH-activating enzyme, type 2 deiodinase (D2), is reversibly turned on by the "Tet-ON" system. Interestingly, increased intracellular TH caused a net shift from oxidative phosphorylation to glycolysis and a consequent increase in the extracellular acidification rate. As a result, mitochondrial ROS production, and both the basal and doxorubicin-induced production of cellular ROS were reduced. Importantly, the expression of a set of antioxidant genes was up-regulated, and, among them, the mitochondrial scavenger Sod2 was specifically induced at transcriptional level by D2mediated TH activation. Finally, we observed that attenuation of oxidative stress and increased levels of SOD2 are key elements of the differentiating cascade triggered by TH and D2, thereby establishing that D2 is essential in coordinating metabolic reprogramming of myocytes during myogenic differentiation. In conclusion, our findings indicate that TH plays a key role in oxidative stress dynamics by regulating ROS generation. Our novel finding that TH and its intracellular metabolism act as mitochondrial detoxifying agents sheds new light on metabolic processes relevant to muscle physiology.
Molecular and cellular endocrinology, Jan 16, 2017
Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development an... more Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development and metabolism of nearly all vertebrate tissues. In skeletal muscle, TH plays a critical role in regulating the function of satellite cells, the bona fide skeletal muscle stem cells. Deiodinases (D2 and D3) have been found to modulate the expression of various TH target genes in satellite cells. Regulation of the expression and activity of the deiodinases constitutes a cell-autonomous, pre-receptor mechanism that controls crucial steps during the various phases of myogenesis. Here, we review the roles of deiodinases in skeletal muscle stem cells, particularly in muscle homeostasis and upon regeneration. We focus on the role of T3 in stem cell functions and in commitment towards lineage progression. We also discuss how deiodinases might be therapeutically exploited to improve satellite-cell-mediated muscle repair in skeletal muscle disorders or injury.
Thyroid : official journal of the American Thyroid Association, Apr 15, 2017
Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular pr... more Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular proliferation and differentiation. The intracellular hormonal environment can be tailored by the deiodinase enzymes, D2 and D3, which catalyze TH activation and inactivation, respectively. In many cellular systems, THs exert well documented stimulatory or inhibitory effects on cell proliferation, however, the molecular mechanisms by which they control rates of cell cycle progression have not yet been entirely clarified. We previously showed that D3-depletion or TH treatment influences the proliferation and survival of basal cell carcinoma (BCC) cells. Surprisingly, we also found that BCC cells express not only sustained levels of D3 but also robust levels of D2. The aim of the present study was to dissect the contribution of D2 to TH metabolism in the BCC context, and to identify the molecular changes associated with cell proliferation and survival induced by TH and mediated by D2 and D3. ...
Introduction Despite a number of review article summarize the positive effect of physical exercis... more Introduction Despite a number of review article summarize the positive effect of physical exercise on the blood lipid profile, sometimes both literature and clinical practice report the inefficacy of physical exercise to improve plasma lipoprotein levels. Because of some studies indicated that the positive effect of physical exercise on blood lipid profile is related to its amount but not to its intensity, we investigated whether a right intervention should only control the physical exercise program or both physical exercise program and daily physical activity. Methods Forty-one sedentary postmenopausal women were enrolled for the study and were evaluated before and after 14 weeks of aerobic training. Blood was collected to measure out plasma levels of triglycerides, total cholesterol (TC) and both low and high-density lipoproteins (LDL, HDL). Anthropometry and body composition analysis included the measurements of body weight and height, waist and hip circumferences and single freq...
Biomedical Engineering Systems and Technologies, 2013
Since the introduction of medical imaging techniques such as MRI, X-Ray, SPECT, PET, large amount... more Since the introduction of medical imaging techniques such as MRI, X-Ray, SPECT, PET, large amounts of medical images have been produced in the different fields of medicine. Most of this data is usually stored either in paper format (stored in clinical records) or in optical disks (given to the patients) and this information is partially uncorrelated with the clinical history of patients. Furthermore, the image processing carried out by the physicians that perform the exam and used to make the diagnosis is unknown for other researchers that further treat the same image. In this paper we propose a system that allows radiologists to share medical images (and their processing) and the associated metadata both within the same medical institute and with other medical institutes located anywhere in the world by using GRID services for data (LFC) and metadata (AMGA) storage. The system is also provided with a semantic layer for describing the stored images through a novel RDF schema, which integrates existing ontologies and vocabularies such as FOAF, Mesh and GeneOntology with new terms related to the image processing part. This enables the correlation of medical images with other clinical information and makes our system fully compatible with the existing systems compliant to semantic web standards.
Understanding Biology Using Peptides, 2006
... Luca D. D'Andrea1, MariaStefania Spagnuolo2, Angela De Stefano1, Marianna Morra1... more ... Luca D. D'Andrea1, MariaStefania Spagnuolo2, Angela De Stefano1, Marianna Morra1, Alessandro Carlucci2, Annarita Del Gatto2, Pasqualina Caso2, Carlo Pedone1, Paolo Abrescia2 and Ettore Benedetti2 1Istituto di Biostrutture e Bioimmagini, CNR, Napoli, 80134, Italy ...
Nucleic Acids Research, 2013
Endocrine-Related Cancer
Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedif... more Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial–mesenchymal transition. Here, we show that D2 is highly expressed in anaplastic compared to papillary thyroid cancer cell lines and that D2-derived T3 is required for ATC cell proliferation. D2 inhibition is associated with G1 growth arrest and induction of cell senescence, together with reduced cell migration and invasive potential. Finally, we found that mutated p5372R(R248W), frequently found in ATC, is able to induce D2 expression in transfected papillary thyroid cancer cells. Our result...
Endocrine-Related Cancer
The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) level... more The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) levels. The two TH-activating deiodinases (type 1 deiodinase and type 2 deiodinase (D2)) are normally expressed in follicular thyroid cells and contribute to overall TH production. During thyroid tumorigenesis, the deiodinase expression profile changes to customize intracellular TH levels to different requirements of cancer cells. Differentiated thyroid cancers overexpress the TH-inactivating type 3 deiodinase (D3), likely to reduce the TH signaling within the tumor. Strikingly, recent evidence suggests that during the late stage of thyroid tumorigenesis, D2 expression raises and this, together with a reduction in D3 expression levels, increases TH intracellular signaling in dedifferentiated thyroid cancers. These findings call into question the different functions of TH in the various stages of thyroid cancers.
Journal of Orthopedic Research and Therapy, 2021
Current Oncology, 2021
Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50... more Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50% of all thyroid cancer-related deaths. During the last two decades, the development of a multimodal personalized approach resulted in an increased survival. Here, we present an unusual case of a 54-year old woman with a paucicellular metastatic ATC, a rare variant of ATC, who was treated with a combination of surgery, radiation therapy and cytotoxic chemotherapy. More than two years later, when the disease was rapidly growing, a combination of lenvatinib and pembrolizumab induced a partial tumor response of lung metastasis that persisted over 18 months. Paucicellular ATC may initially show a less aggressive behavior compared to other histological ATC variants. However, over the time, its clinical course can rapidly progress like common ATC. The combination of lenvatinib and pembrolizumab was effective as a salvage therapy for a long period of time.
Metabolites, 2021
Skeletal muscle atrophy is a condition associated with various physiological and pathophysiologic... more Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin–proteasome. Thyroid hormone (TH) plays a key role in these conditions. Indeed, skeletal muscle is among the principal TH target tissue, where TH regulates proliferation, metabolism, differentiation, homeostasis, and growth. In physiological conditions, TH stimulates both protein synthesis and degradation, and an alteration in TH levels is often responsible for a specific myopathy. Intracellular TH concentrations are modulated in skeletal muscle by a family of enzymes named deiodinases; in particular, in musc...
Endocrinology, 2021
Hormones are key drivers of cancer development, and alteration of the intratumoral concentration ... more Hormones are key drivers of cancer development, and alteration of the intratumoral concentration of thyroid hormone (TH) is a common feature of many human neoplasias. Besides the systemic control of TH levels, the expression and activity of deiodinases constitute a major mechanism for the cell-autonomous, prereceptoral control of TH action. The action of deiodinases ensures tight control of TH availability at intracellular level in a time- and tissue-specific manner, and alterations in deiodinase expression are frequent in tumors. Research over the past decades has shown that in cancer cells, a complex and dynamic expression of deiodinases is orchestrated by a network of growth factors, oncogenic proteins, and miRNA. It has become increasingly evident that this fine regulation exposes cancer cells to a dynamic concentration of TH that is functional to stimulate or inhibit various cellular functions. This review summarizes recent advances in the identification of the complex interpla...
Nature Communications, 2020
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Proceedings of the International Conference on Health Informatics, 2011
Large amounts of images (SPECT, PET, scintigraphy) in the nuclear medicine field have been routin... more Large amounts of images (SPECT, PET, scintigraphy) in the nuclear medicine field have been routinely produced in the last decades. In this paper we propose an image management system that allows nuclear medicine physicians to share the acquired images and the associated metadata both locally (i.e. within the same medical institute) and globally with other nuclear medicine physicians located anywhere in the world by using GRID services for data (LFC) and metadata (AMGA) storage. The proposed system guarantees medical data protection by anonymization that removes most sensitive data for unauthorized users, and encryption, that guarantees data protection when it is stored at remote sites. Another important issue is that often nuclear medicine data is associated with other medical data (e.g. neurological data) for diagnosis and therapy follow-up. In order to correlate images with other clinical information, the common metadata are enriched by developing a controlled vocabulary, which integrates known standards such as FOAF, CCR and GeneOntology. All the metadata are stored in an RDF (Resource Description Framework) repository in order to make the system fully compatible with existing metadata storage systems following the semantic web's philosophy.
Cancers, 2020
Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissu... more Type 2 deiodinase (D2), the principal activator of thyroid hormone (TH) signaling in target tissues, is expressed in cutaneous squamous cell carcinomas (SCCs) during late tumorigenesis, and its repression attenuates the invasiveness and metastatic spread of SCC. Although D2 plays multiple roles in cancer progression, nothing is known about the mechanisms regulating D2 in cancer. To address this issue, we investigated putative upstream regulators of D2 in keratinocyte carcinomas. We found that the expression of D2 in SCC cells is positively regulated by the NANOG transcription factor, whose expression, besides being causally linked to embryonic stemness, is associated with many human cancers. We also found that NANOG binds to the D2 promoter and enhances D2 transcription. Notably, blockage of D2 activity reduced NANOG-induced cell migration as well as the expression of key genes involved in epithelial–mesenchymal transition in SCC cells. In conclusion, our study reveals a link among ...
Thyroid, 2020
Thyroid hormones (THs) are key regulators of development, tissue differentiation and maintenance ... more Thyroid hormones (THs) are key regulators of development, tissue differentiation and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 deiodinase (D3), the TH inactivating enzyme. Here, we demonstrate that D3 is dynamically regulated during epidermal ontogenesis. To investigate the function of D3 in a post-developmental context, we used a mouse model of conditional epidermal-specific D3 depletion. Loss of D3 resulted in tissue hypoplasia and enhanced epidermal differentiation in a cell-autonomous manner. Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Furthermore, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were up-regulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular T3 levels. Notably, loss of D3 reduced the clearance of systemic TH in vivo, thereby demonstrating the critical requirement for epidermal D3 in the maintenance of TH homeostasis. In conclusion, our results show that the D3 enzyme is a key TH-signaling component in the skin thereby providing a striking example of a physiological context for deiodinase-mediated TH metabolism, as well as a rationale for therapeutic manipulation of deiodinases in patho-physiological contexts.
Nature Communications, 2019
Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report th... more Epithelial tumor progression often involves epithelial-mesenchymal transition (EMT). We report that increased intracellular levels of thyroid hormone (TH) promote the EMT and malignant evolution of squamous cell carcinoma (SCC) cells. TH induces the EMT by transcriptionally up-regulating ZEB-1, mesenchymal genes and metalloproteases and suppresses E-cadherin expression. Accordingly, in human SCC, elevated D2 (the T3-producing enzyme) correlates with tumor grade and is associated with an increased risk of postsurgical relapse and shorter disease-free survival. These data provide the first in vivo demonstration that TH and its activating enzyme, D2, play an effective role not only in the EMT but also in the entire neoplastic cascade starting from tumor formation up to metastatic transformation, and supports the concept that TH is an EMT promoter. Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH sig...
Redox Biology, 2019
Thyroid hormone (TH) is a key metabolic regulator that acts by coordinating short-and long-term e... more Thyroid hormone (TH) is a key metabolic regulator that acts by coordinating short-and long-term energy needs. Accordingly, significant metabolic changes are observed depending on thyroid status. Although it is established that hyperthyroidism augments basal energy consumption, thus resulting in an enhanced metabolic state, the net effects on cellular respiration and generation of reactive oxygen species (ROS) remain unclear. To elucidate the effects of augmented TH signal in muscle cells, we generated a doxycycline-inducible cell line in which the expression of the TH-activating enzyme, type 2 deiodinase (D2), is reversibly turned on by the "Tet-ON" system. Interestingly, increased intracellular TH caused a net shift from oxidative phosphorylation to glycolysis and a consequent increase in the extracellular acidification rate. As a result, mitochondrial ROS production, and both the basal and doxorubicin-induced production of cellular ROS were reduced. Importantly, the expression of a set of antioxidant genes was up-regulated, and, among them, the mitochondrial scavenger Sod2 was specifically induced at transcriptional level by D2mediated TH activation. Finally, we observed that attenuation of oxidative stress and increased levels of SOD2 are key elements of the differentiating cascade triggered by TH and D2, thereby establishing that D2 is essential in coordinating metabolic reprogramming of myocytes during myogenic differentiation. In conclusion, our findings indicate that TH plays a key role in oxidative stress dynamics by regulating ROS generation. Our novel finding that TH and its intracellular metabolism act as mitochondrial detoxifying agents sheds new light on metabolic processes relevant to muscle physiology.
Molecular and cellular endocrinology, Jan 16, 2017
Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development an... more Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development and metabolism of nearly all vertebrate tissues. In skeletal muscle, TH plays a critical role in regulating the function of satellite cells, the bona fide skeletal muscle stem cells. Deiodinases (D2 and D3) have been found to modulate the expression of various TH target genes in satellite cells. Regulation of the expression and activity of the deiodinases constitutes a cell-autonomous, pre-receptor mechanism that controls crucial steps during the various phases of myogenesis. Here, we review the roles of deiodinases in skeletal muscle stem cells, particularly in muscle homeostasis and upon regeneration. We focus on the role of T3 in stem cell functions and in commitment towards lineage progression. We also discuss how deiodinases might be therapeutically exploited to improve satellite-cell-mediated muscle repair in skeletal muscle disorders or injury.
Thyroid : official journal of the American Thyroid Association, Apr 15, 2017
Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular pr... more Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular proliferation and differentiation. The intracellular hormonal environment can be tailored by the deiodinase enzymes, D2 and D3, which catalyze TH activation and inactivation, respectively. In many cellular systems, THs exert well documented stimulatory or inhibitory effects on cell proliferation, however, the molecular mechanisms by which they control rates of cell cycle progression have not yet been entirely clarified. We previously showed that D3-depletion or TH treatment influences the proliferation and survival of basal cell carcinoma (BCC) cells. Surprisingly, we also found that BCC cells express not only sustained levels of D3 but also robust levels of D2. The aim of the present study was to dissect the contribution of D2 to TH metabolism in the BCC context, and to identify the molecular changes associated with cell proliferation and survival induced by TH and mediated by D2 and D3. ...
Introduction Despite a number of review article summarize the positive effect of physical exercis... more Introduction Despite a number of review article summarize the positive effect of physical exercise on the blood lipid profile, sometimes both literature and clinical practice report the inefficacy of physical exercise to improve plasma lipoprotein levels. Because of some studies indicated that the positive effect of physical exercise on blood lipid profile is related to its amount but not to its intensity, we investigated whether a right intervention should only control the physical exercise program or both physical exercise program and daily physical activity. Methods Forty-one sedentary postmenopausal women were enrolled for the study and were evaluated before and after 14 weeks of aerobic training. Blood was collected to measure out plasma levels of triglycerides, total cholesterol (TC) and both low and high-density lipoproteins (LDL, HDL). Anthropometry and body composition analysis included the measurements of body weight and height, waist and hip circumferences and single freq...
Biomedical Engineering Systems and Technologies, 2013
Since the introduction of medical imaging techniques such as MRI, X-Ray, SPECT, PET, large amount... more Since the introduction of medical imaging techniques such as MRI, X-Ray, SPECT, PET, large amounts of medical images have been produced in the different fields of medicine. Most of this data is usually stored either in paper format (stored in clinical records) or in optical disks (given to the patients) and this information is partially uncorrelated with the clinical history of patients. Furthermore, the image processing carried out by the physicians that perform the exam and used to make the diagnosis is unknown for other researchers that further treat the same image. In this paper we propose a system that allows radiologists to share medical images (and their processing) and the associated metadata both within the same medical institute and with other medical institutes located anywhere in the world by using GRID services for data (LFC) and metadata (AMGA) storage. The system is also provided with a semantic layer for describing the stored images through a novel RDF schema, which integrates existing ontologies and vocabularies such as FOAF, Mesh and GeneOntology with new terms related to the image processing part. This enables the correlation of medical images with other clinical information and makes our system fully compatible with the existing systems compliant to semantic web standards.
Understanding Biology Using Peptides, 2006
... Luca D. D'Andrea1, MariaStefania Spagnuolo2, Angela De Stefano1, Marianna Morra1... more ... Luca D. D'Andrea1, MariaStefania Spagnuolo2, Angela De Stefano1, Marianna Morra1, Alessandro Carlucci2, Annarita Del Gatto2, Pasqualina Caso2, Carlo Pedone1, Paolo Abrescia2 and Ettore Benedetti2 1Istituto di Biostrutture e Bioimmagini, CNR, Napoli, 80134, Italy ...
Nucleic Acids Research, 2013