133 results on '"Dentice, M."'
Search Results
2. Quercetin and its derivative Q2 modulate chromatin dynamics in adipogenesis and Q2 prevents obesity and metabolic disorders in rats
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Nettore IC (1), Rocca C (2), Mancino G (1), Albano L(3, Amelio D (2), Grande F(5), Puoci F(5), Pasqua T(2), Desiderio S(1), Mazza R(2), Terracciano D(3), Colao A(1), Bèguinot F(3, Russo GL(6), Dentice M(1), Macchia PE(1), Sinicropi MS(5), Angelone T(2, Ungaro P(4)., Nettore, I. C., Rocca, C., Mancino, G., Albano, L., Amelio, D., Grande, F., Puoci, F., Pasqua, T., Desiderio, S., Mazza, R., Terracciano, D., Colao, A., Beguinot, F., Russo, G. L., Dentice, M., Macchia, P. E., Sinicropi, M. S., Angelone, T., and Ungaro, P.
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Male ,0301 basic medicine ,Cell Survival ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biological Availability ,Diet, High-Fat ,Biochemistry ,Chromatin remodeling ,Epigenesis, Genetic ,Histones ,Mice ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,3T3-L1 Cells ,Adipocytes ,Animals ,Benzopyrans ,Obesity ,Rats, Wistar ,Molecular Biology ,Epigenomics ,Adipogenesi ,Adipogenesis ,Nutrition and Dietetics ,biology ,Chemistry ,Epigenetic ,Polyphenols ,Lipid Metabolism ,Chromatin ,Cell biology ,PPAR gamma ,030104 developmental biology ,Histone ,030220 oncology & carcinogenesis ,CCAAT-Enhancer-Binding Proteins ,Histone modifications ,biology.protein ,Demethylase ,Quercetin ,Anti-Obesity Agents ,Histone modification ,Chromatin immunoprecipitation - Abstract
Recently the attention of the scientific community has focused on the ability of polyphenols to counteract adverse epigenetic regulation involved in the development of complex conditions such as obesity. The aim of this study was to investigate the epigenetic mechanisms underlying the anti-adiposity effect of Quercetin (3,3′,4′,5,7-pentahydroxyflavone) and of one of its derivatives, Q2 in which the OH groups have been replaced by acetyl groups. In 3 T3-L1 preadipocytes, Quercetin and Q2 treatment induce chromatin remodeling and histone modifications at the 5′ regulatory region of the two main adipogenic genes, c/EBPα and PPARγ. Chromatin immunoprecipitation assays revealed a concomitant increase of histone H3 di-methylation at Lys9, a typical mark of repressed gene promoters, and a decrease of histone H3 di-methylation at Lys 4, a mark of active transcription. At the same time, both compounds inhibited histone demethylase LSD1 recruitment to the 5′ region of c/EBPα and PPARγ genes, a necessary step for adipogenesis. The final effect is a significant reduction in c/EBPα and PPARγ gene expression and attenuated adipogenesis. Q2 supplementation in rats reduced the gain in body weight and in white adipose tissue, as well as the increase in adipocyte size determined by high fat diet. Moreover, Q2 improved dyslipidemia, glucose tolerance and decreased the hepatic lipid accumulation by activating the expression of beta-oxidation related genes. Our data suggest that Q2, as well as Quercetin, has the potential to revert the unfavorable epigenomic profiles associated with obesity onset. This opens the possibility to use these compounds in targeted prevention strategies against obesity.
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- 2019
3. AXL is a predictor of poor survival and of resistance to anti-EGFR therapy in RAS wild-type metastatic colorectal cancer
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Cardone C., Blauensteiner B., Moreno-Viedma V., Martini G., Simeon V., Vitiello P. P., Ciardiello D., Belli V., Matrone N., Troiani T., Morgillo F., Zito Marino F., Dentice M., Nappi A., Boccaccino A., Antoniotti C., Cremolini C., Pietrantonio F., Prager G. W., Normanno N., Maiello E., Argiles G., Elez E., Signoriello G., Franco R., Falcone A., Tabernero J., Sibilia M., Ciardiello F., Martinelli E., ZITO MARINO, Federica, Cardone, Claudia, Blauensteiner, Bernadette, Moreno-Viedma, Veronica, Martini, Giulia, Simeon, Vittorio, Vitiello, Pietro P, Ciardiello, Davide, Belli, Valentina, Matrone, Nunzia, Troiani, Teresa, Morgillo, Floriana, Zito Marino, Federica, Dentice, Monica, Nappi, Annarita, Boccaccino, Alessandra, Antoniotti, Carlotta, Cremolini, Chiara, Pietrantonio, Filippo, Prager, Gerald W, Normanno, Nicola, Maiello, Evaristo, Argiles, Guillem, Elez, Elena, Signoriello, Giuseppe, Franco, Renato, Falcone, Alfredo, Tabernero, Josep, Sibilia, Maria, Ciardiello, Fortunato, Martinelli, Erika, Cardone, C., Blauensteiner, B., Moreno-Viedma, V., Martini, G., Simeon, V., Vitiello, P. P., Ciardiello, D., Belli, V., Matrone, N., Troiani, T., Morgillo, F., Zito Marino, F., Dentice, M., Nappi, A., Boccaccino, A., Antoniotti, C., Cremolini, C., Pietrantonio, F., Prager, G. W., Normanno, N., Maiello, E., Argiles, G., Elez, E., Signoriello, G., Franco, R., Falcone, A., Tabernero, J., Sibilia, M., Ciardiello, F., Martinelli, E., and ZITO MARINO, Federica
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Population ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Growth factor receptor ,Internal medicine ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,education ,education.field_of_study ,Cetuximab ,business.industry ,AXL ,EGFR resistance ,RAS WT ,Receptor Protein-Tyrosine Kinases ,Transfection ,medicine.disease ,Xenograft Model Antitumor Assays ,Axl Receptor Tyrosine Kinase ,Blockade ,ErbB Receptors ,030104 developmental biology ,Genes, ras ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Immunohistochemistry ,business ,Colorectal Neoplasms ,Biomarkers ,medicine.drug - Abstract
Background RAS mutations are the only validated biomarkers in metastatic colorectal cancer (mCRC) for anti-epidermal growth factor receptor (EGFR) therapy. Limited clinical information is available on AXL expression, marker of epithelial to mesenchymal transition, in mCRC. Methods AXL was retrospectively assessed by immunohistochemistry in 307 patients. RAS wild-type (WT) patients (N = 136) received first-line anti-EGFR–based therapy; RAS mutant patients (N = 171) received anti-angiogenic–based regimens. Preclinical experiments were performed using human RAS WT CRC cell lines and xenograft models. AXL RNA levels were assessed in a cohort of patients with available samples at baseline and at progression to anti-EGFR treatment and in the GSE5851 dataset. Results AXL was expressed in 55/307 tumour tissues, correlating with worse survival in the overall population (AXL-positive, 23.7 months; AXL-negative, 30.8 months; HR, 1.455, P = 0.032) and in RAS WT patients (AXL-positive, 23.0 months; AXL-negative, 35.8 months; HR,1.780, P = 0.032). Progression-free survival (PFS) in the RAS WT cohort was shorter in the AXL-positive cohort (6.2 months versus 12.1 months; HR, 1.796, P = 0.013). Three-dimensional cultures obtained from a patient following anti-EGFR therapy resulted AXL-positive, showing resistance to anti-EGFR drugs and sensitivity to AXL inhibition. AXL transfection in CRC cell lines induced AXL overexpression and resistance to the EGFR blockade. At progression to cetuximab, 2/10 SW48-tumour xenograft mice showed AXL expression. Consistently, AXL RNA levels increased in 5/7 patients following anti-EGFR therapy. Moreover, in the GSE5851 dataset higher AXL RNA levels correlated with worse PFS with cetuximab in KRAS-exon2 WT chemorefractory patients. Conclusions AXL is a marker of poor prognosis in mCRC with consistent clinical and preclinical evidences of involvement in primary and acquired resistance to anti-EGFR drugs in RAS WT patients.
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- 2020
4. Activation and inactivation of thyroid hormone by deiodinases: Local action with general consequences
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Gereben, B., Zeöld, A., Dentice, M., Salvatore, D., and Bianco, A. C.
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- 2008
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5. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains
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Di Rienzo, M., primary, Antonioli, M., additional, Fusco, C., additional, Liu, Y., additional, Mari, M., additional, Orhon, I., additional, Refolo, G., additional, Germani, F., additional, Corazzari, M., additional, Romagnoli, A., additional, Ciccosanti, F., additional, Mandriani, B., additional, Pellico, M. T., additional, De La Torre, R., additional, Ding, H., additional, Dentice, M., additional, Neri, M., additional, Ferlini, A., additional, Reggiori, F., additional, Kulesz-Martin, M., additional, Piacentini, M., additional, Merla, G., additional, and Fimia, G. M., additional
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- 2019
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6. Deiodination in cancer growth: the role of type III deiodinase
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Sibilio, A., Raffaele Ambrosio, Bonelli, C., Stefano, M. A., Torre, V., Dentice, M., Salvatore, D., Sibilio, A., Ambrosio, R., Bonelli, C., De Stefano, Ma, Torre, V, Dentice, Monica, and Salvatore, Domenico
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Neoplasms, Hormone-Dependent ,Triiodothyronine, Reverse ,Iodide Peroxidase ,Neoplasm Proteins ,Enzyme Activation ,Gene Expression Regulation, Neoplastic ,Thyroxine ,Cell Transformation, Neoplastic ,Hypothyroidism ,Organ Specificity ,Enzyme Induction ,Neoplasms ,Humans ,Triiodothyronine ,Molecular Targeted Therapy ,Cell Division ,Subcellular Fractions - Abstract
Thyroid hormone (TH) is a pleiotropic agent that has widespread biological functions, i.e., it controls cellular growth, tissue development and homeostasis and neoplastic transformation. Suitable TH levels are critical for the development of various types of tissues and are essential for the regulation of metabolic processes throughout life. The serum concentrations of TH affect its biological activity. Moreover, at tissue level, TH action is regulated by the expression and activity of deiodinases, i.e., the enzymes that mediate the metabolic pathways by activating and/or inactivating TH. The type I and II deiodinases (D1 and D2) initiate TH action by converting thyroxine (T4) into the active TH form (T3), whereas type III deiodinase (D3) mediates the local attenuation of TH by converting T4 and T3 into the inactive metabolites rT3 and T2, respectively. The deiodinase system is a potent mechanism of pre-receptoral control of TH action; it is often altered in such pathological conditions as cancer. D3 is widely expressed in embryonic tissues and in placenta, where it blocks excessive maternal-to-fetal transfer of TH. In contrast, during late neonatal and adult life, D3 is expressed mainly in the central nervous system and skin. Interestingly, D3 expression is re-activated in various types of human cancers. Here we review recent evidence that D3 expression plays a crucial role in human carcinogenesis, and speculate as to its complex role in the regulation of cell proliferation in several neoplastic contexts. It is conceivable that the local modulation of TH action via deiodinases is a powerful molecular tool to manipulate the intracellular TH status, thus influencing the growth and maintenance of selected hormone-dependent cancers.
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- 2012
7. Il gas naturale nel condizionamento - La valutazione economica delle pompe di calore ad azionamento termico
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VANOLI, RAFFAELE, DENTICE M., Vanoli, Raffaele, and Dentice, M.
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- 2000
8. ANALISI ENERGETICA ED ECONOMICA DI ULCUNE UTENZE DEL TERZIARIO UBICATE NELLA REGIONE CAMPANIA: ALBERGHI ED OSPEDALI
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VANOLI, RAFFAELE, DENTICE M., SASSO M., SIBILIO S., BURGANI E., FALCONE G., PASTORE E., Vanoli, Raffaele, Dentice, M., Sasso, M., Sibilio, S., Burgani, E., Falcone, G., and Pastore, E.
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- 2000
9. APPLICAZIONI DI ENERGETICA - INTRODUZIONE ALL'ANALISI TECNICO-ECONOMICA DI SISTEMI DI RISPARMIO ENERGETICO
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VANOLI, RAFFAELE, DENTICE M., SASSO M., SIBILIO S., Vanoli, Raffaele, Dentice, M., Sasso, M., and Sibilio, S.
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- 1999
10. Epigenetic control of type 2 and 3 deiodinases in myogenesis: role of Lysine-specific Demethylase enzyme and FoxO3
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Ambrosio, R., primary, Damiano, V., additional, Sibilio, A., additional, De Stefano, M. A., additional, Avvedimento, V. E., additional, Salvatore, D., additional, and Dentice, M., additional
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- 2013
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11. Activation and inactivation of thyroid hormone by deiodinases: Local action with general consequences
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Gereben, B., primary, Zeöld, A., additional, Dentice, M., additional, Salvatore, D., additional, and Bianco, A. C., additional
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- 2007
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12. Suppression of HMGA2 Protein Synthesis Could Be a Tool for the Therapy of Well Differentiated Liposarcomas Overexpressing HMGA2
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Pentimalli, F., Dentice, M., Fedele, M., Pierantoni, G. M., Cito, L., Pallante, P., Santoro, M., Viglietto, G., Dal Cin, P., and Alfredo Fusco
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Atypical lipomatous tumors (ALTs)/well-differentiated liposarcomas represent a distinctive subset of mesenchymal neoplasms featuring mature adipocytic proliferation. These tumors are characterized cytogenetically by the presence of supernumerary ring and/or long marker chromosomes that contain several copies of the chromosomal region 12q13-15, in which the HMGA2 gene is located. Deregulation of the HMGA2 gene is a common molecular alteration implicated in the development of a variety of benign tumors, such as lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. In this study, we observed HMGA2 overexpression in 7 of 12 ALT primary cell cultures examined. Subsequently, we generated an adenovirus containing the HMGA2 gene in the antisense orientation (Ad-A2as) to study the effect of HMGA2 protein suppression in ALT cells. The infection of six ALT cells, three of which were positive for HMGA2 expression, resulted in growth inhibition coupled with a significant increase in apoptosis. In addition, the growth of the ALT cells negative for HMGA2 expression was not affected by the infection with either the Ad-A2as or the control virus. On the basis of these findings, the targeting of the HMGA2 protein expression may represent a promising approach for treating the well-differentiated liposarcomas resistant to conventional therapies.
13. Overexpression of proteins HMGA1 induces cell cycle deregulation and apoptosis in normal rat thyroid cells
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Fedele, M., Pierantoni, G. M., Berlingieri, M. T., Battista, S., Gustavo Baldassarre, Munshi, N., Dentice, M., Thanos, D., Santoro, M., Viglietto, G., and Fusco, A.
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DNA, Complementary ,Cell Cycle ,High Mobility Group Proteins ,Thyroid Gland ,Gene Expression ,Apoptosis ,Transfection ,Peptide Mapping ,Rats ,Cell Transformation, Neoplastic ,Cyclins ,CDC2 Protein Kinase ,Animals ,Protein Isoforms ,Cell Division - Abstract
The high mobility group (HMG) proteins (HMGA1a, HMGA1b, and HMGA2) bind to DNA and interact with various transcriptional factors. Therefore, they play an important role in chromatin organization. HMGA protein expression is low in normal adult tissues, but abundant during embryonic development and in several experimental and human tumors. Blockage of HMGA expression inhibits the transformation of rat thyroid PC Cl 3 cells treated with oncogene-carrying retroviruses, thus implicating HMGA in rat thyroid transformation. To better understand the role of HMGA and to establish whether its up-regulated expression is sufficient to induce the transformed phenotype, we generated PC Cl 3 cells that overexpress the protein. We demonstrate that HMGA1b protein overexpression does not transform normal rat thyroid PC Cl 3 cells, but it deregulates their cell cycle: cells enter S-phase earlier and the G(2)-M transition is delayed. HMGA1-overexpressing cells undergo apoptosis through a pathway involving caspase-3 activation, probably consequent to the conflict between mitogenic pressure and the inability to proceed through the cell cycle. Using various HMGA1b gene mutations, we found that the third AT-hook domain and the acetylation site K60 are the protein regions required for induction of apoptosis in PC Cl 3 cells. In conclusion, although HMGA1 protein overexpression is associated with the malignant phenotype of rat and human thyroid cells, it does not transform normal thyroid cells in culture but leads them to programmed cell death.
14. Nutrient-Dependent Mitochondrial Fission Enhances Osteoblast Function
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Ciro Menale, Giovanna Trinchese, Immacolata Aiello, Giulia Scalia, Monica Dentice, Maria Pina Mollica, Nal Ae Yoon, Sabrina Diano, Menale, C., Trinchese, G., Aiello, I., Scalia, G., Dentice, M., Mollica, M. P., Yoon, N. A., and Diano, S.
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osteoblasts ,glucose ,palmitate ,mitochondrial fission ,metabolism ,bioenergetics ,Nutrition and Dietetics ,osteoblast ,bioenergetic ,Food Science - Abstract
Background: The bone synthesizing function of osteoblasts (OBs) is a highly demanding energy process that requires nutrients. However, how nutrient availability affects OBs behavior and bone mineralization remain to be fully understood. Methods: MC3T3-E1 cell line and primary OBs (OBs) cultures were treated with physiological levels of glucose (G; 5.5 mM) alone or with the addition of palmitic acid (G+PA) at different concentrations. Mitochondria morphology and activity were evaluated by fluorescence microscopy, qPCR, and oxygen consumption rate (OCR) measurement, and OBs function was assessed by mineralization assay. Results: The addition of non-lipotoxic levels of 25 μM PA to G increased mineralization in OBs. G+25 μM PA exposure reduced mitochondria size in OBs, which was associated with increased activation of dynamin-related protein 1, a mitochondrial fission protein, enhanced mitochondria OCR and ATP production, and increased expression of oxidative phosphorylation genes. Treatment with Mdivi-1, a putative inhibitor of mitochondrial fission, reduced osteogenesis and mitochondrial respiration in OBs. Conclusions: Our results revealed that OBs function was enhanced in the presence of glucose and PA at 25 μM. This was associated with increased OBs mitochondrial respiration and dynamics. These results suggest a role for nutrient availability in bone physiology and pathophysiology.
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- 2023
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15. A Type 2 Deiodinase-Dependent Increase in Vegfa Mediates Myoblast-Endothelial Cell Crosstalk During Skeletal Muscle Regeneration
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Simone Magagnin Wajner, Monica Dentice, Cristina Luongo, Annunziata Gaetana Cicatiello, Raffaele Ambrosio, Diane E. Handy, P. Reed Larsen, Ashley N. Ogawa-Wong, Colleen Carmody, Domenico Salvatore, Xingxing An, Ann Marie Zavacki, An, X., Ogawa-Wong, A., Carmody, C., Ambrosio, R., Cicatiello, A. G., Luongo, C., Salvatore, D., Handy, D. E., Larsen, P. R., Wajner, S. M., Dentice, M., and Zavacki, A. M.
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deiodinase ,Male ,Vascular Endothelial Growth Factor A ,Myoblasts, Skeletal ,Endocrinology, Diabetes and Metabolism ,Human Umbilical Vein Endothelial Cell ,Deiodinase ,Neovascularization, Physiologic ,DIO2 ,030209 endocrinology & metabolism ,Muscle Development ,Iodide Peroxidase ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Cell Movement ,satellite cell ,Paracrine Communication ,medicine ,Regeneration ,Myocyte ,skeletal muscle ,Muscle, Skeletal ,Cell Proliferation ,Mice, Knockout ,biology ,Animal ,Chemistry ,angiogenesi ,Skeletal muscle ,thyroid hormone ,VEGF ,Up-Regulation ,Cell biology ,Mice, Inbred C57BL ,Endothelial stem cell ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Stem cell ,Intracellular ,Human ,Signal Transduction - Abstract
Background: The type 2 deiodinase (DIO2) converts thyroxine to 3,3′,5-triiodothyronine (T3), modulating intracellular T3. An increase in DIO2 within muscle stem cells during skeletal muscle regeneration leads to T3-dependent potentiation of differentiation. The muscle stem cell niche comprises numerous cell types, which coordinate the regeneration process. For example, muscle stem cells provide secretory signals stimulating endothelial cell-mediated vascular repair, and, in turn, endothelial cells promote muscle stem differentiation. We hypothesized that Dio2 loss in muscle stem cells directly impairs muscle stem cell-endothelial cell communication, leading to downstream disruption of endothelial cell function. Methods: We assessed the production of proangiogenic factors in differentiated C2C12 cells and in a C2C12 cell line without Dio2 (D2KO C2C12) by real-time quantitative-polymerase chain reaction and enzyme-linked immunosorbent assay. Conditioned medium (CM) was collected daily in parallel to evaluate its effects on human umbilical vein endothelial cell (HUVEC) proliferation, migration and chemotaxis, and vascular network formation. The effects of T3-treatment on vascular endothelial growth factor (Vegfa) mRNA expression in C2C12 cells and mouse muscle were assessed. Chromatin immunoprecipitation (ChIP) identified thyroid hormone receptor (TR) binding to the Vegfa gene. Using mice with a targeted disruption of Dio2 (D2KO mice), we determined endothelial cell number by immunohistochemistry/flow cytometry and evaluated related gene expression in both uninjured and injured skeletal muscle. Results: In differentiated D2KO C2C12 cells, Vegfa expression was 46% of wildtype (WT) C2C12 cells, while secreted VEGF was 45%. D2KO C2C12 CM exhibited significantly less proangiogenic effects on HUVECs. In vitro and in vivo T3 treatment of C2C12 cells and WT mice, and ChIP using antibodies against TRα, indicated that Vegfa is a direct genomic T3 target. In uninjured D2KO soleus muscle, Vegfa expression was decreased by 28% compared with WT mice, while endothelial cell numbers were decreased by 48%. Seven days after skeletal muscle injury, D2KO mice had 36% fewer endothelial cells, coinciding with an 83% decrease in Vegfa expression in fluorescence-activated cell sorting purified muscle stem cells. Conclusion: Dio2 loss in the muscle stem cell impairs muscle stem cell-endothelial cell crosstalk via changes in the T3-responsive gene Vegfa, leading to downstream impairment of endothelial cell function both in vitro and in vivo.
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- 2021
16. Thyroid hormone regulates glutamine metabolism and anaplerotic fluxes by inducing mitochondrial glutamate aminotransferase GPT2
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Annunziata Gaetana Cicatiello, Serena Sagliocchi, Annarita Nappi, Emery Di Cicco, Caterina Miro, Melania Murolo, Mariano Stornaiuolo, Monica Dentice, Cicatiello, Annunziata Gaetana, Sagliocchi, Serena, Nappi, Annarita, Di Cicco, Emery, Miro, Caterina, Murolo, Melania, Stornaiuolo, Mariano, Dentice, Monica, Cicatiello, A. G., Sagliocchi, S., Nappi, A., Di Cicco, E., Miro, C., Murolo, M., Stornaiuolo, M., and Dentice, M.
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Thyroid Hormones ,GPT2 ,Glutamine ,Intellectual Disability ,glutamine metabolism ,Humans ,Alanine Transaminase ,skeletal muscle ,thyroid hormone ,type 2 deiodinase ,General Biochemistry, Genetics and Molecular Biology ,Transaminases - Abstract
Thyroid hormones (THs) are key metabolic regulators coordinating short- and long-term energy needs. In skeletal muscle, THs modulate energy metabolism in pathophysiological conditions. Indeed, hypo- and hyperthyroidism are leading causes of muscle weakness and strength; however, the metabolic pathways underlying these effects are still poorly understood. Using molecular, biochemical, and isotope-tracing approaches combined with mass spectrometry and denervation experiments, we find that THs regulate glutamine metabolism and anaplerotic fluxes by up-regulating the glutamate pyruvate transaminase 2 (GPT2) gene. In humans, GPT2 autosomal recessive mutations cause a neurological syndrome characterized by intellectual disability, microcephaly, and progressive motor symptoms. Here, we demonstrate a role of the TH/GPT2 axis in skeletal muscle in which it regulates muscle weight and fiber diameter in resting and atrophic conditions and results in protection from muscle loss during atrophy. These results describe an anabolic route by which THs rewire glutamine metabolism toward the maintenance of muscle mass.
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- 2021
17. Thyroid hormone and androgen signals mutually interplay and enhance inflammation and tumorigenic activation of tumor microenvironment in prostate cancer
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Caterina Miro, Angelo Di Giovanni, Melania Murolo, Annunziata Gaetana Cicatiello, Annarita Nappi, Serena Sagliocchi, Emery Di Cicco, Francesco Morra, Angela Celetti, Francesco Pacifico, Ciro Imbimbo, Felice Crocetto, Monica Dentice, Miro, C., Di Giovanni, A., Murolo, M., Cicatiello, A. G., Nappi, A., Sagliocchi, S., Di Cicco, E., Morra, F., Celetti, A., Pacifico, F., Imbimbo, C., Crocetto, F., and Dentice, M.
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Inflammation ,Male ,Cancer Research ,Thyroid Hormones ,Prostate cancer ,Carcinogenesis ,Prostatic Hyperplasia ,Prostatic Neoplasms ,Oncology ,Receptors, Androgen ,Cell Line, Tumor ,Deiodinase ,Androgens ,Tumor Microenvironment ,Humans - Abstract
Prostate Cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in males and the fifth leading cause of death worldwide. The majority of PCas are androgen-sensitive, with a significant up-regulation of Androgen Receptor (AR) that causes a stimulatory effect on growth and progression of cancer cells. For this reason, the first-line therapy for PCa is androgen ablation, even if it ultimately fails due to the onset of hormone-refractory state, in which the malignant cells do not sense the androgen signal anymore. Besides androgens, a growing number of evidence suggests that Thyroid Hormones (THs) mediate tumor-promoting effects in a variety of human cancers, as Epithelial-to-Mesenchymal Transition (EMT), invasion and metastasis and also stimulation of angiogenesis and tumor metabolism. Moreover, epidemiological studies demonstrated an increased risk for PCa in patients with lower levels of Thyreotropin (TSH). Here, we investigated if intracellular TH metabolism affects Benign Prostatic Hyperplasia (BPH) and PCa formation and progression. We found that the intracellular TH metabolism is a crucial determinant of PCa behavior. We observed that a dynamic stage-specific expression of the THs modulating enzymes, the deiodinases, is required for the progression of BPH to PCa malignancy. By acting simultaneously on epithelial cancer cells and fibroblasts, THs exert a proliferative and pro-inflammatory effect cooperating with androgens. These findings suggest that androgens and THs may interplay and mediate a coordinate effect on human PCa formation and progression. In light of our results, future perspective could be to explore the potential benefits of THs intracellular modulators aimed to counteract PCa progression.
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- 2021
18. Selective Inhibition of Genomic and Non-Genomic Effects of Thyroid Hormone Regulates Muscle Cell Differentiation and Metabolic Behavior
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Caterina Miro, Mariano Stornaiuolo, Maddalena Raia, Annunziata Gaetana Cicatiello, Emery Di Cicco, Monica Dentice, Annarita Nappi, Melania Murolo, Serena Sagliocchi, Lucia D’Esposito, Rossella Di Paola, Nappi, A., Murolo, M., Sagliocchi, S., Miro, C., Cicatiello, A. G., Di Cicco, E., Di Paola, R., Raia, M., D'Esposito, L., Stornaiuolo, M., and Dentice, M.
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0301 basic medicine ,deiodinase ,Myoblast proliferation ,Thyroid Hormones ,QH301-705.5 ,Deiodinase ,DIO2 ,Muscle Cell ,030209 endocrinology & metabolism ,Iodide Peroxidase ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,genomic and non-genomic action ,medicine ,Gene silencing ,Myocyte ,Animals ,Biology (General) ,Physical and Theoretical Chemistry ,Muscle, Skeletal ,QD1-999 ,Molecular Biology ,Spectroscopy ,Muscle Cells ,biology ,Muscle cell differentiation ,Animal ,Organic Chemistry ,Integrin beta3 ,Skeletal muscle ,Cell Differentiation ,General Medicine ,thyroid hormone ,Computer Science Applications ,Cell biology ,Chemistry ,030104 developmental biology ,medicine.anatomical_structure ,Nuclear receptor ,biology.protein - Abstract
Thyroid hormones (THs) are key regulators of different biological processes. Their action involves genomic and non-genomic mechanisms, which together mediate the final effects of TH in target tissues. However, the proportion of the two processes and their contribution to the TH-mediated effects are still poorly understood. Skeletal muscle is a classical target tissue for TH, which regulates muscle strength and contraction, as well as energetic metabolism of myofibers. Here we address the different contribution of genomic and non-genomic action of TH in skeletal muscle cells by specifically silencing the deiodinase Dio2 or the β3-Integrin expression via CRISPR/Cas9 technology. We found that myoblast proliferation is inversely regulated by integrin signal and the D2-dependent TH activation. Similarly, inhibition of the nuclear receptor action reduced myoblast proliferation, confirming that genomic action of TH attenuates proliferative rates. Contrarily, genomic and non-genomic signals promote muscle differentiation and the regulation of the redox state. Taken together, our data reveal that integration of genomic and non-genomic signal pathways finely regulates skeletal muscle physiology. These findings not only contribute to the understanding of the mechanisms involved in TH modulation of muscle physiology but also add insight into the interplay between different mechanisms of action of TH in muscle cells.
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- 2021
19. Germ Line Mutations in the Thyroid Hormone Receptor Alpha Gene Predispose to Cutaneous Tags and Melanocytic Nevi
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Annarita Nappi, Silvia Parisi, Carla Moran, Domenico Salvatore, Erik Schoenmakers, Mehul T. Dattani, V. Krishna K. Chatterjee, W. Edward Visser, Emery Di Cicco, Raffaele Ambrosio, P. Todd, Monica Dentice, Greta Lyons, Internal Medicine, Di Cicco, E., Moran, C., Visser, W. E., Nappi, A., Schoenmakers, E., Todd, P., Lyons, G., Dattani, M., Ambrosio, R., Parisi, S., Salvatore, D., Chatterjee, K., Dentice, M., Schoenmakers, Erik [0000-0003-0674-8282], Chatterjee, Krishna [0000-0002-2654-8854], and Apollo - University of Cambridge Repository
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Adult ,Male ,deiodinase ,Pathology ,medicine.medical_specialty ,skin ,Skin Neoplasms ,Adolescent ,Genotype ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,resistance to thyroid hormone α ,Thyroid Economy: Regulation, Cell Biology, and Thyroid Hormone Metabolism and Action ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Cyclin D1 ,SDG 3 - Good Health and Well-being ,medicine ,Humans ,Basal cell carcinoma ,Genetic Predisposition to Disease ,thyroid hormone receptor α ,Receptor ,Child ,Germ-Line Mutation ,Nevus, Pigmented ,business.industry ,Melanoma ,Thyroid ,Cell Cycle ,thyroid hormone action ,Middle Aged ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,Phenotype ,Nuclear receptor ,Dysplasia ,030220 oncology & carcinogenesis ,Female ,business ,Hormone ,Thyroid Hormone Receptors alpha - Abstract
Background: Many physiological effects of thyroid hormone (TH) are mediated by its canonical action via nuclear receptors (TH receptor α and β [TRα and TRβ]) to regulate transcription of target genes. Heterozygous dominant negative mutations in human TRα mediate resistance to thyroid hormone alpha (RTHα), characterized by features of hypothyroidism (e.g., skeletal dysplasia, neurodevelopmental retardation, constipation) in specific tissues, but near-normal circulating TH concentrations. Hitherto, 41 RTHα cases have been recorded worldwide. Methods: RTHα cases (n = 10) attending a single center underwent cutaneous assessment, recording skin lesions. Lesions excised from different RTHα patients were analyzed histologically and profiled for cellular markers of proliferation and oncogenic potential. Proliferative characteristics of dermal fibroblasts and inducible pluripotent stem cell (iPSC)-derived keratinocytes from patients and control subjects were analyzed. Results: Multiple skin tags and nevi were recorded in all cases, mainly in the head and neck area with a predilection for flexures. The affected patients had highly deleterious mutations (p.E403X, p.E403K, p.F397fs406X, p.A382PfsX7) involving TRα1 alone or mild/moderate loss-of-function mutations (p.A263V, p.L274P) common to TRα1 and TRα2 isoforms. In four patients, although lesions excised for cosmetic reasons were benign intradermal melanocytic nevi histologically, they significantly overexpressed markers of cell proliferation (K17, cyclin D1) and type 3 deiodinase. In addition, oncogenic markers typical of basal cell carcinoma (Gli-1, Gli-2, Ptch-1, n = 2 cases) and melanoma (c-kit, MAGE, CDK4, n = 1) were markedly upregulated in skin lesions. Cell cycle progression and proliferation of TRα mutation-containing dermal fibroblasts and iPSC-derived keratinocytes from patients were markedly increased. Conclusions: Our observations highlight frequent occurrence of skin tags and benign melanocytic nevi in RTHα, with cutaneous cells from patients being in a hyperproliferative state. Such excess of skin lesions, including nevi expressing oncogenic markers, indicates that dermatologic surveillance of RTHα patients, monitoring lesions for features that are suspicious for neoplastic change, is warranted.
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- 2021
20. Thyroid Hormone Enhances Angiogenesis and the Warburg Effect in Squamous Cell Carcinomas
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Melania Murolo, Serena Sagliocchi, Domenico Salvatore, Mariano Stornaiuolo, Sandra Albanese, Ann Marie Zavacki, Emery Di Cicco, Sara Amiranda, Marcello Mancini, Caterina Miro, Annarita Nappi, Annunziata Gaetana Cicatiello, Valentina Belli, Monica Dentice, Teresa Troiani, Miro, C., Nappi, A., Cicatiello, A. G., Di Cicco, E., Sagliocchi, S., Murolo, M., Belli, V., Troiani, T., Albanese, S., Amiranda, S., Zavacki, A. M., Stornaiuolo, M., Mancini, M., Salvatore, D., and Dentice, M.
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0301 basic medicine ,squamous cell carcinoma ,Cancer Research ,Cell type ,Angiogenesis ,Cell ,Biology ,Article ,03 medical and health sciences ,angiogenesis ,0302 clinical medicine ,Deiodinase ,medicine ,Glycolysis ,RC254-282 ,thyroid hormones ,Cancer ,deiodinases ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Warburg effect ,Angiogenesi ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Hormone - Abstract
Simple Summary Cancer cells rewire their metabolism to promote growth, survival, proliferation, and long-term maintenance. Aerobic glycolysis is a prominent trait of many cancers; contextually, glutamine addiction, enhanced glucose uptake and aerobic glycolysis sustain the metabolic needs of rapidly proliferating cancer cells. Thyroid hormone (TH) is a positive regulator of tumor progression and metastatic conversion of squamous cell carcinoma (SCC). Accordingly, overexpression of the TH activating enzyme, D2, is associated with metastatic SCC. The aim of our study was to assess the ability of TH and its activating enzyme in promoting key tracts of cancer progression such as angiogenesis, response to hypoxia and metabolic adaptation. By performing in vivo and in vitro studies, we demonstrate that TH induces VEGF-A in cancer cells and fosters aerobic glycolysis inducing pro-glycolytic mediators, thus implying that TH signal attenuation represents a therapeutic tool to contrast tumor angiogenesis and tumor progression. Abstract Cancer angiogenesis is required to support energetic demand and metabolic stress, particularly during conditions of hypoxia. Coupled to neo-vasculogenesis, cancer cells rewire metabolic programs to sustain growth, survival and long-term maintenance. Thyroid hormone (TH) signaling regulates growth and differentiation in a variety of cell types and tissues, thus modulating hyper proliferative processes such as cancer. Herein, we report that TH coordinates a global program of metabolic reprogramming and induces angiogenesis through up-regulation of the VEGF-A gene, which results in the enhanced proliferation of tumor endothelial cells. In vivo conditional depletion of the TH activating enzyme in a mouse model of cutaneous squamous cell carcinoma (SCC) reduces the concentration of TH in the tumoral cells and results in impaired VEGF-A production and attenuated angiogenesis. In addition, we found that TH induces the expression of the glycolytic genes and fosters lactate production, which are key traits of the Warburg effect. Taken together, our results reveal a TH–VEGF-A–HIF1α regulatory axis leading to enhanced angiogenesis and glycolytic flux, which may represent a target for SCC therapy.
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- 2021
21. A Global Loss of Dio2 Leads to Unexpected Changes in Function and Fiber Types of Slow Skeletal Muscle in Male Mice
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Marian J. Zuidwijk, Travis Petersen, Benjamin Sager, Warner S. Simonides, Rob Janssen, Amy J. Wagers, Cristina Luongo, Cecilia Martin, Alessandro Marsili, Monica Dentice, Adriana Roginski Guetter, Anita Boelen, P. Reed Larsen, Ashley N. Ogawa-Wong, J. Enrique Silva, Domenico Salvatore, Colleen Carmody, Neil M. Neumann, Ann Marie Zavacki, Elizabeth Y Wu, Kaman Hau, Sylvia Bogaards, Physiology, ACS - Heart failure & arrhythmias, ACS - Pulmonary hypertension & thrombosis, Endocrinology Laboratory, AGEM - Endocrinology, metabolism and nutrition, Carmody, C., Ogawa-Wong, A. N., Martin, C., Luongo, C., Zuidwijk, M., Sager, B., Petersen, T., Roginski Guetter, A., Janssen, R., Wu, E. Y., Bogaards, S., Neumann, N. M., Hau, K., Marsili, A., Boelen, A., Silva, J. E., Dentice, M., Salvatore, Domenico, Wagers, A. J., Larsen, P. R., Simonides, W. S., and Zavacki, A. M.
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Male ,0301 basic medicine ,medicine.medical_specialty ,Gene Expression ,DIO2 ,030209 endocrinology & metabolism ,Iodide Peroxidase ,Cell Line ,Myoblasts ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Precursor cell ,medicine ,Animals ,Myocyte ,Muscle, Skeletal ,Research Articles ,Mice, Knockout ,Soleus muscle ,Chemistry ,Myogenesis ,Skeletal muscle ,Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ,Mice, Inbred C57BL ,Thyroxine ,Muscle Fibers, Slow-Twitch ,030104 developmental biology ,medicine.anatomical_structure ,Triiodothyronine ,C2C12 ,Immunostaining ,Muscle Contraction - Abstract
The type 2 iodothyronine-deiodinase (D2) enzyme converts T(4) to T(3), and mice deficient in this enzyme [D2 knockout (D2KO) mice] have decreased T(3) derived from T(4) in skeletal muscle despite normal circulating T(3) levels. Because slow skeletal muscle is particularly susceptible to changes in T(3) levels, we expected D2 inactivation to result in more pronounced slow-muscle characteristics in the soleus muscle, mirroring hypothyroidism. However, ex vivo studies of D2KO soleus revealed higher rates of twitch contraction and relaxation and reduced resistance to fatigue. Immunostaining of D2KO soleus showed that these properties were associated with changes in muscle fiber type composition, including a marked increase in the number of fast, glycolytic type IIB fibers. D2KO soleus muscle fibers had a larger cross-sectional area, and this correlated with increased myonuclear accretion in myotubes formed from D2KO skeletal muscle precursor cells differentiated in vitro. Consistent with our functional findings, D2KO soleus gene expression was markedly different from that in hypothyroid wild-type (WT) mice. Comparison of gene expression between euthyroid WT and D2KO mice indicated that PGC-1α, a T(3)-dependent regulator of slow muscle fiber type, was decreased by ∼50% in D2KO soleus. Disruption of Dio2 in the C2C12 myoblast cell line led to a significant decrease in PGC-1α expression and a faster muscle phenotype upon differentiation. These results indicate that D2 loss leads to significant changes in soleus contractile function and fiber type composition that are inconsistent with local hypothyroidism and suggest that reduced levels of PCG-1α may contribute to the observed phenotypical changes.
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- 2019
22. Local hyperthyroidism promotes pancreatic acinar cell proliferation during acute pancreatitis
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Andrew P. Hills, Stephen Myers, Sabrina Sonda, Domenico Salvatore, Rolf Graf, Monica Dentice, Theresia Reding, Ermanno Malagola, Rong Chen, Enrica Saponara, Marta Bombardo, Malagola, E., Chen, R., Bombardo, M., Saponara, E., Dentice, M., Salvatore, Domenico, Reding, T., Myers, S., Hills, A. P., Graf, R., and Sonda, S.
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Male ,deiodinase ,0301 basic medicine ,Context (language use) ,Acinar Cells ,Hyperthyroidism ,Iodide Peroxidase ,Histone Deacetylases ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Transforming Growth Factor beta ,medicine ,Animals ,Protein kinase B ,Cell Proliferation ,Mice, Knockout ,acute pancreatiti ,thyroid hormones ,Acinar cell proliferation ,business.industry ,Thyroid ,Receptor, Transforming Growth Factor-beta Type II ,acinar proliferation ,medicine.disease ,T3 ,Pancreas, Exocrine ,Up-Regulation ,Mice, Inbred C57BL ,Disease Models, Animal ,Thyroxine ,030104 developmental biology ,medicine.anatomical_structure ,Pancreatitis ,030220 oncology & carcinogenesis ,Cancer research ,Triiodothyronine ,Acute pancreatitis ,Pancreas ,business ,Proto-Oncogene Proteins c-akt ,Ceruletide ,Signal Transduction ,Hormone - Abstract
Proliferation of pancreatic acinar cells is a critical process in the pathophysiology of pancreatic diseases, because limited or defective proliferation is associated with organ dysfunction and patient morbidity. In this context, elucidating the signalling pathways that trigger and sustain acinar proliferation is pivotal to develop therapeutic interventions promoting the regenerative process of the organ. In this study we used genetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones to elucidate their role in acinar proliferation following caerulein-mediated acute pancreatitis in mice. In addition, molecular mechanisms mediating the effects of thyroid hormones were identified by genetic and pharmacological inactivation of selected signalling pathways.In this study we demonstrated that levels of the thyroid hormone 3,3',5-triiodo-l-thyronine (T3) transiently increased in the pancreas during acute pancreatitis. Moreover, by using genetic and pharmacological approaches to manipulate both local and systemic levels of thyroid hormones, we showed that T3 was required to promote proliferation of pancreatic acinar cells, without affecting the extent of tissue damage or inflammatory infiltration.Finally, upon genetic and pharmacological inactivation of selected signalling pathways, we demonstrated that T3 exerted its mitogenic effect on acinar cells via a tightly controlled action on different molecular effectors, including histone deacetylase, AKT, and TGFβ signalling.In conclusion, our data suggest that local availability of T3 in the pancreas is required to promote acinar cell proliferation and provide the rationale to exploit thyroid hormone signalling to enhance pancreatic regeneration. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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- 2019
23. Intracellular control of thyroid hormone in epithelial tumorigenesis
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Monica Dentice, Giuseppina Mancino, Caterina Miro, Emery Di Cicco, Mancino, G., Di Cicco, E., Miro, C., and Dentice, M.
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0301 basic medicine ,business.industry ,Colorectal cancer ,Endocrinology, Diabetes and Metabolism ,Thyroid ,Cancer ,medicine.disease ,medicine.disease_cause ,Colon cancer ,3. Good health ,Thyroid hormone ,03 medical and health sciences ,medicine.drug_formulation_ingredient ,030104 developmental biology ,medicine.anatomical_structure ,Deiodinase ,Cancer cell ,Cancer research ,Skin cancer ,Medicine ,Neoplastic transformation ,business ,Carcinogenesis ,Thyroid extract ,Hormone - Abstract
Interest in thyroid hormone (TH) in cancer was first aroused by the demonstration, over a century ago, that breast cancer responded to thyroid extract treatment. This suggested that TH was a key regulator of tumorigenesis. However, the role of TH in the complex process of neoplastic transformation long remained obscure. Interest in the link between TH and cancer was renewed when it became clear that TH receptors and modulators are often altered in cancerous tissues and that modulation of TH might foster cancer cell expansion. Studies in two different epithelial cancers, namely the Basal Cell Carcinoma of the skin and the colon cancer have provided molecular insight the role of TH modulation at intracellular level in tumor formation, thus prompting interest in tissue-specific TH modulation as an anti-tumoral agent. Since then a large body of data has accumulated on this topic and the aim of this brief review is to try to draw together the evidence pointing to a general mechanism by which TH interferes with oncogenic pathways, thus affecting tumoral formation.
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- 2018
24. Treatment of cutaneous melanoma harboring smo p.Gln216arg mutation with imiquimod: An old drug with new results
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Fortunato Ciardiello, Michele Caraglia, Stefania Napolitano, Annarita Nappi, Gabriella Brancaccio, Vincenzo De Falco, Domenico Salvatore, Monica Dentice, Teresa Troiani, Emilio Francesco Giunta, Giuseppe Argenziano, Renato Franco, Valentina Belli, Davide Ciardiello, Caterina Miro, Troiani, T., Napolitano, S., Brancaccio, G., Belli, V., Nappi, A., Miro, C., Salvatore, D., Dentice, M., Caraglia, M., Franco, R., Giunta, E. F., De Falco, V., Ciardiello, D., Ciardiello, F., Argenziano, G., Troiani, Teresa, Napolitano, Stefania, Brancaccio, Gabriella, Belli, Valentina, Nappi, Annarita, Miro, Caterina, Salvatore, Domenico, Dentice, Monica, Caraglia, Michele, Franco, Renato, Giunta, Emilio Francesco, De Falco, Vincenzo, Ciardiello, Davide, Ciardiello, Fortunato, and Argenziano, Giuseppe
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Druggability ,lcsh:Medicine ,Medicine (miscellaneous) ,Case Report ,Imiquimod ,Disease ,medicine.disease_cause ,Hedgehog pathway ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Medicine ,Melanoma ,030304 developmental biology ,0303 health sciences ,Mutation ,business.industry ,lcsh:R ,SMO ,medicine.disease ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Cancer research ,Skin cancer ,business ,medicine.drug - Abstract
Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options. Here we report, for the first time to our knowledge, a clinical case where a melanoma patient harboring the SMO p.Gln216Arg mutation has been treated with imiquimod, showing a complete and durable response. To better explain this outstanding response to the treatment, we transfected a melanoma cell line (MeWo) with the SMO p.Gln216Arg mutation in order to evaluate its role in response to the imiquimod treatment. Moreover, to better demonstrate that the antitumor activity of imiquimod was due to its role in suppressing the oncogenic SMO signaling pathway, independently of its immune modulating function, an in vivo experiment has been performed. This clinical case opens up a new scenario for the treatment of melanoma patients identifying a new potentially druggable target.
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- 2021
25. The NANOG Transcription Factor Induces Type 2 Deiodinase Expression and Regulates the Intracellular Activation of Thyroid Hormone in Keratinocyte Carcinomas
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Serena Sagliocchi, Tommaso Porcelli, Annarita Nappi, Mariano Stornaiuolo, Caterina Miro, Daniela Di Girolamo, Cristina Luongo, Maria Angela De Stefano, Monica Dentice, Emery Di Cicco, Annunziata Gaetana Cicatiello, Raffaele Ambrosio, Giuseppina Mancino, Nappi, A., Di Cicco, E., Miro, C., Cicatiello, A. G., Sagliocchi, S., Mancino, G., Ambrosio, R., Luongo, C., Di Girolamo, D., De Stefano, M. A., Porcelli, T., Stornaiuolo, M., and Dentice, M.
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0301 basic medicine ,Homeobox protein NANOG ,Cancer Research ,Deiodinase ,Biology ,medicine.disease_cause ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Transcription factor ,skin cancer ,Activator (genetics) ,Thyroid ,deiodinases ,Cell migration ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,thyroid hormone ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Carcinogenesis ,Hormone - Abstract
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&ndash, mesenchymal transition in SCC cells. In conclusion, our study reveals a link among endogenous endocrine regulators of cancer, thyroid hormone and its activating enzyme, and the NANOG regulator of cancer biology. These findings could provide the basis for the development of TH inhibitors as context-dependent anti-tumor agents.
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- 2020
26. Author Correction: Thyroid hormone induces progression and invasiveness of squamous cell carcinomas by promoting a ZEB-1/E-cadherin switch (Nature Communications, (2019), 10, 1, (5410), 10.1038/s41467-019-13140-2)
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Miro, Caterina, di Cicco, Emery, Ambrosio, Raffaele, Mancino, Giuseppina, di Girolamo, Daniela, Cicatiello, Annunziata Gaetana, Sagliocchi, Serena, Nappi, Annarita, de Stefano, Maria Angela, Luongo, Cristina, Antonini, Dario, Visconte, Feliciano, Varricchio, Silvia, Ilardi, Gennaro, del Vecchio, Luigi, Staibano, Stefania, Boelen, Anita, Blanpain, Cedric, Missero, Caterina, Salvatore, Domenico, Dentice, Monica, Miro, C., Di Cicco, E., Ambrosio, R., Mancino, G., Di Girolamo, D., Cicatiello, A. G., Sagliocchi, S., Nappi, A., De Stefano, M. A., Luongo, C., Antonini, D., Visconte, F., Varricchio, S., Ilardi, G., Del Vecchio, L., Staibano, S., Boelen, A., Blanpain, C., Missero, C., Salvatore, D., Dentice, M., Laboratory for Endocrinology, and AGEM - Endocrinology, metabolism and nutrition
- Abstract
The original version of this Article contained an error in the author affiliations. Silvia Varricchio, Gennaro Ilardi and Stefania Staibanow were incorrectly associated with ‘Department of Public Health, University of Naples "Federico II", Naples, Italy’ instead of the correct ‘Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Naples, Italy.’ This has now been corrected in both the PDF and HTML versions of the Article.
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- 2020
27. The Thyroid Hormone Inactivator Enzyme, Type 3 Deiodinase, Is Essential for Coordination of Keratinocyte Growth and Differentiation
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Emery Di Cicco, Mariano Stornaiuolo, Cristina Luongo, Pietro Formisano, Giuseppina Mancino, Daniela Di Girolamo, Caterina Miro, Federica Saracino, Maria Angela De Stefano, Tommaso Porcelli, Monica Dentice, Annarita Sibilio, Annarita Nappi, Giuseppe Perruolo, Melania Murolo, Serena Sagliocchi, Annunziata Gaetana Cicatiello, Raffaele Ambrosio, Mancino, G., Sibilio, A., Luongo, C., Di Cicco, E., Miro, C., Cicatiello, A. G., Nappi, A., Sagliocchi, S., Ambrosio, R., De Stefano, M. A., Di Girolamo, D., Porcelli, T., Murolo, M., Saracino, F., Perruolo, G., Formisano, P., Stornaiuolo, M., and Dentice, M.
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Keratinocytes ,deiodinase ,Thyroid Hormones ,Endocrinology, Diabetes and Metabolism ,Deiodinase ,030209 endocrinology & metabolism ,Context (language use) ,Biology ,Iodide Peroxidase ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Endocrinology ,medicine ,Animals ,Homeostasis ,Mice, Knockout ,Triiodothyronine ,integumentary system ,Epidermis (botany) ,deiodinases ,Cell Differentiation ,skin homeostasi ,Hair follicle ,thyroid hormone ,Cell biology ,medicine.anatomical_structure ,skin homeostasis ,030220 oncology & carcinogenesis ,biology.protein ,Epidermis ,Keratinocyte ,Hormone - Abstract
Background: 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. Methods: To investigate the function of D3 in a postdevelopmental 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. Results: Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Further, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were upregulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular triiodothyronine 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. Conclusion: 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 pathophysiological contexts.
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- 2020
28. Thyroid Hormone Hyposensitivity: From Genotype to Phenotype and Back
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Giuditta Rurale, Emery Di Cicco, Monica Dentice, Domenico Salvatore, Luca Persani, Federica Marelli, Cristina Luongo, Rurale, G., Cicco, E. D., Dentice, M., Salvatore, D., Persani, L., Marelli, F., and Luongo, C.
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0301 basic medicine ,thyroid hormone metabolism defects ,Endocrinology, Diabetes and Metabolism ,Mini Review ,DIO2 ,030209 endocrinology & metabolism ,Biology ,Bioinformatics ,Thyroid function tests ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,thyroid hormones action defects ,thyroid hormone metabolism defect ,medicine ,thyroid hormone hyposensitivity ,Receptor ,thyroid hormone cell membrane transport defect ,Gene ,thyroid hormones ,lcsh:RC648-665 ,medicine.diagnostic_test ,Thyroid ,Membrane transport ,thyroid hormone ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,thyroid hormone cell membrane transport defects ,Hormone - Abstract
Thyroid hormone action defects (THADs) have been classically considered conditions of impaired sensitivity to thyroid hormone (TH). They were originally referring to alterations in TH receptor genes (THRA and THRB), but the discovery of genetic mutations and polymorphisms causing alterations in cell membrane transport (e.g., MCT8) and metabolism (e.g., SECISBP2, DIO2) led recently to a new and broader definition of TH hyposensitivity (THH), including not only THADs but all defects that could interfere with the activity of TH. Due to the different functions and tissue-specific expression of these genes, affected patients exhibit highly variable phenotypes. Some of them are characterized by a tissue hypothyroidism or well-recognizable alterations in the thyroid function tests (TFTs), whereas others display a combination of hypo- and hyperthyroid manifestations with normal or only subtle biochemical defects. The huge effort of basic research has greatly aided the comprehension of the molecular mechanisms underlying THADs, dissecting the morphological and functional alterations on target tissues, and defining the related-changes in the biochemical profile. In this review, we describe different pictures in which a specific alteration in the TFTs (TSH, T4, and T3 levels) is caused by defects in a specific gene. Altogether these findings can help clinicians to early recognize and diagnose THH and to perform a more precise genetic screening and therapeutic intervention. On the other hand, the identification of new genetic variants will allow the generation of cell-based and animal models to give novel insight into thyroid physiology and establish new therapeutic interventions.
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- 2020
29. Deiodinases and their intricate role in thyroid hormone homeostasis
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Domenico Salvatore, Cristina Luongo, Monica Dentice, Luongo, C., Dentice, M., and Salvatore, Domenico
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0301 basic medicine ,medicine.medical_specialty ,Thyroid Hormones ,Endocrinology, Diabetes and Metabolism ,Cell ,Deiodinase ,030209 endocrinology & metabolism ,Iodide Peroxidase ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Animals ,Homeostasis ,Humans ,In patient ,biology ,business.industry ,Thyroid ,Tissue level ,Thyroid Diseases ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,business ,Intracellular ,Hormone ,Signal Transduction - Abstract
The deiodinase family of enzymes mediates the activation and inactivation of thyroid hormone. The role of these enzymes in the regulation of the systemic concentrations of thyroid hormone is well established and underpins the treatment of common thyroid diseases. Interest in this field has increased in the past 10 years as the deiodinases became implicated in tissue development and homeostasis, as well as in the pathogenesis of a wide range of human diseases. Three deiodinases have been identified, namely, types 1, 2 and 3 iodothyronine deiodinases, which differ in their catalytic properties and tissue distribution. Notably, the expression of these enzymes changes during the lifetime of an individual in relation to the different needs of each organ and to ageing. The systemic homeostatic role of deiodinases clearly emerges during changes in serum concentrations of thyroid hormone, as seen in patients with thyroid dysfunction. By contrast, the role of deiodinases at the tissue level allows thyroid hormone signalling to be finely tuned within a given cell in a precise time–space window without perturbing serum concentrations of thyroid hormone. This Review maps the overall functional role of the deiodinases and explores challenges and novel opportunities arising from the expanding knowledge of these ‘master’ components of the thyroid homeostatic system. This Review discusses the two main functions of the human deiodinases: the homeostatic control of plasma concentrations of thyroid hormone and the control of intracellular T3 concentrations.
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- 2019
30. Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains
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Fulvio Reggiori, Monica Dentice, Marcella Neri, Manuela Antonioli, M. Di Rienzo, Idil Orhon, Fabiola Ciccosanti, Alessandra Ferlini, Giuseppe Merla, F. Germani, Mauro Piacentini, Barbara Mandriani, H. Ding, Giulia Refolo, Muriel Mari, Maria Teresa Pellico, Marco Corazzari, Molly Kulesz-Martin, Carmela Fusco, Gian Maria Fimia, Yuangang Liu, Alessandra Romagnoli, R. De La Torre, Center for Liver, Digestive and Metabolic Diseases (CLDM), Microbes in Health and Disease (MHD), Di Rienzo, M., Antonioli, M., Fusco, C., Liu, Y., Mari, M., Orhon, I., Refolo, G., Germani, F., Corazzari, M., Romagnoli, A., Ciccosanti, F., Mandriani, B., Pellico, M. T., De La Torre, R., Ding, H., Dentice, M., Neri, M., Ferlini, A., Reggiori, F., Kulesz-Martin, M., Piacentini, M., Merla, G., and Fimia, G. M.
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Plasma protein binding ,LS3_11 ,RNA, Small Interfering/metabolism ,Muscular Dystrophies ,Myoblasts ,Tripartite Motif Proteins ,Limb-Girdle ,Mice ,0302 clinical medicine ,Ubiquitin ,Myocyte ,Autophagy-Related Protein-1 Homolog ,Autophagy-Related Protein-1 Homolog/metabolism ,Research Articles ,adaptor proteins, signal transducing ,animals ,autophagy-related protein-1 homolog ,cell line ,cell transdifferentiation ,humans ,lysine ,mice ,mice, knockout ,muscular dystrophies, limb-girdle ,myoblasts ,protein binding ,rna interference ,rna, small interfering ,ubiquitin-protein ligases ,ubiquitination ,autophagy ,Mice, Knockout ,Muscular Dystrophies, Limb-Girdle/metabolism ,0303 health sciences ,Multidisciplinary ,biology ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Signal transducing adaptor protein ,Adaptor Proteins ,SciAdv r-articles ,Muscle atrophy ,Ubiquitin ligase ,Cell biology ,030220 oncology & carcinogenesis ,RNA Interference ,medicine.symptom ,Research Article ,Signal Transduction ,Lysine/metabolism ,Protein Binding ,Settore BIO/06 ,Knockout ,Ubiquitin-Protein Ligases ,Ubiquitin-Protein Ligases/antagonists & inhibitors ,Small Interfering ,NO ,Cell Line ,03 medical and health sciences ,Adaptor Proteins, Signal Transducing/antagonists & inhibitors ,medicine ,Autophagy ,Animals ,Humans ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Lysine ,Signal Transducing ,Ubiquitination ,Cell Biology ,ULK1 ,Muscular Dystrophies, Limb-Girdle ,Cell Transdifferentiation ,biology.protein ,RNA ,RNA, Small Interfering ,Atrophy ,Myoblasts/cytology ,Transcription Factors - Abstract
Muscular dystrophy-associated mutations of TRIM32 impair ULK1-dependent autophagy response during muscle atrophy., Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32’s ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.
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- 2019
31. Thyroid hormone induces progression and invasiveness of squamous cell carcinomas by promoting a ZEB-1/E-cadherin switch
- Author
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Serena Sagliocchi, Cédric Blanpain, Gennaro Ilardi, Silvia Varricchio, Caterina Missero, Anita Boelen, Caterina Miro, Stefania Staibano, Daniela Di Girolamo, Annunziata Gaetana Cicatiello, Raffaele Ambrosio, Dario Antonini, Annarita Nappi, Feliciano Visconte, Cristina Luongo, Emery Di Cicco, Domenico Salvatore, Luigi Del Vecchio, Monica Dentice, Giuseppina Mancino, Maria Angela De Stefano, Endocrinology Laboratory, AGEM - Endocrinology, metabolism and nutrition, Miro, C., Di Cicco, E., Ambrosio, R., Mancino, G., Di Girolamo, D., Cicatiello, A. G., Sagliocchi, S., Nappi, A., De Stefano, M. A., Luongo, C., Antonini, D., Visconte, F., Varricchio, S., Ilardi, G., Del Vecchio, L., Staibano, S., Boelen, A., Blanpain, C., Missero, C., Salvatore, D., and Dentice, M.
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0301 basic medicine ,Cell biology ,Molecular biology ,Science ,Cell ,General Physics and Astronomy ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Endocrinology ,0302 clinical medicine ,medicine ,Carcinoma ,Chimie ,Epithelial–mesenchymal transition ,lcsh:Science ,Cancer ,Multidisciplinary ,Physique ,Cadherin ,Thyroid ,Mesenchymal stem cell ,General Chemistry ,Astronomie ,medicine.disease ,3. Good health ,Technologie de l'environnement, contrôle de la pollution ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,lcsh:Q ,Hormone - Abstract
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 signaling may suppress the metastatic proclivity of SCC., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2019
32. The thyroid hormone activating enzyme, type 2 deiodinase, induces myogenic differentiation by regulating mitochondrial metabolism and reducing oxidative stress
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Annunziata Gaetana Cicatiello, Raffaele Ambrosio, Domenico Salvatore, Monica Dentice, Maddalena Raia, Daniela Di Girolamo, Emery Di Cicco, Cristina Luongo, Giuseppina Mancino, Maria Angela De Stefano, Ann Marie Zavacki, Simona Paladino, Annarita Nappi, Caterina Miro, Ashley N. Ogawa-Wong, Serena Sagliocchi, Sagliocchi, Serena, Cicatiello, A. G., Di Cicco, E., Ambrosio, R., Miro, C., Di Girolamo, D., Nappi, Annarita, Mancino, G., De Stefano, M. A., Luongo, C., Raia, M., Ogawa-Wong, A. N., Zavacki, A. M., Paladino, S., Salvatore, Domenico, and Dentice, M.
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0301 basic medicine ,Mitochondrial ROS ,Male ,Thyroid Hormones ,Cellular respiration ,Clinical Biochemistry ,Deiodinase ,SOD2 ,Oxidative phosphorylation ,medicine.disease_cause ,Muscle Development ,Biochemistry ,Iodide Peroxidase ,Antioxidants ,Oxidative Phosphorylation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,lcsh:QH301-705.5 ,chemistry.chemical_classification ,Reactive oxygen species ,lcsh:R5-920 ,biology ,Superoxide Dismutase ,Organic Chemistry ,Cell biology ,Mitochondria ,Oxidative Stress ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,biology.protein ,Reactive Oxygen Species ,lcsh:Medicine (General) ,Glycolysis ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Oxidative stress ,Intracellular ,Research Paper - Abstract
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 D2-mediated 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.
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- 2019
33. Activated Thyroid Hormone Promotes Differentiation and Chemotherapeutic Sensitization of Colorectal Cancer Stem Cells by Regulating Wnt and BMP4 Signaling
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Raffaele Ambrosio, Cristina Luongo, Matilde Todaro, Domenico Salvatore, R. Carollo, Antonina Benfante, Giorgio Stassi, Veronica Catalano, Monica Dentice, Catalano, Veronica, Dentice, Monica, Ambrosio, Raffaele, Luongo, Cristina, Carollo, Rosachiara, Benfante, Antonina, Todaro, Matilde, Stassi, Giorgio, Salvatore, Domenico, Catalano, V., Dentice, M., Ambrosio, R., Luongo, C., Carollo, R., Benfante, A., Todaro, M., Stassi, G., and Salvatore, D.
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Male ,0301 basic medicine ,Thyroid Hormones ,endocrine system ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,Cellular differentiation ,Deiodinase ,Bone Morphogenetic Protein 4 ,Colorectal Neoplasm ,Mice ,03 medical and health sciences ,Cancer stem cell ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Thyroid Hormone ,Wnt Signaling Pathway ,Hormone activity ,Thyroid hormone receptor ,biology ,Animal ,Thyroid ,Wnt signaling pathway ,Cell Differentiation ,Middle Aged ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Neoplastic Stem Cells ,Cancer research ,biology.protein ,Neoplastic Stem Cell ,Colorectal Neoplasms ,Human ,Signal Transduction ,Hormone - Abstract
Thyroid hormone is a pleiotropic factor that controls many cellular processes in multiple cell types such as cancer stem cells (CSC). Thyroid hormone concentrations in the blood are stable, but the action of the deiodinases (D2–D3) provides cell-specific regulation of thyroid hormone activity. Deregulation of deiodinase function and thyroid hormone status has been implicated in tumorigenesis. Therefore, we investigated the role of thyroid hormone metabolism and signaling in colorectal CSCs (CR-CSC), where deiodinases control cell division and chemosensitivity. We found that increased intracellular thyroid hormone concentration through D3 depletion induced cell differentiation and sharply mitigated tumor formation. Upregulated BMP4 expression and concomitantly attenuated Wnt signaling accompanied these effects. Furthermore, we demonstrate that BMP4 is a direct thyroid hormone target and is involved in a positive autoregulatory feedback loop that modulates thyroid hormone signaling. Collectively, our findings highlight a cell-autonomous metabolic mechanism by which CR-CSCs exploit thyroid hormone signaling to facilitate their self-renewal potential and suggest that drug-induced cell differentiation may represent a promising therapy for preventing CSC expansion and tumor progression. Cancer Res; 76(5); 1237–44. ©2015 AACR.
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- 2016
34. The Hepatoprotective Effect of Taurisolo, a Nutraceutical Enriched in Resveratrol and Polyphenols, Involves Activation of Mitochondrial Metabolism in Mice Liver
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Eduardo Sommella, Nadia Badolati, Serena Sagliocchi, Alessandro Di Minno, Gian Carlo Tenore, Mariano Stornaiuolo, Pietro Campiglia, Ettore Novellino, Emanuela Salviati, Raffaello Masselli, Monica Dentice, Badolati, N., Masselli, R., Sommella, E., Sagliocchi, S., Di Minno, A, Salviati, E., Campiglia, P., Dentice, M., Tenore, G. C., Stornaiuolo, M., and Novellino, E.
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Polyphenol ,0301 basic medicine ,Antioxidant ,Physiology ,medicine.medical_treatment ,Clinical Biochemistry ,Resveratrol ,Pharmacology ,liver ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Nonalcoholic fatty liver disease ,medicine ,Molecular Biology ,polyphenols ,nutraceuticals ,chemistry.chemical_classification ,Catabolism ,Cholesterol ,lcsh:RM1-950 ,Fatty acid ,Antioxidants ,Liver ,Mitochondria ,Nutraceuticals ,Polyphenols ,Cell Biology ,medicine.disease ,mitochondria ,lcsh:Therapeutics. Pharmacology ,antioxidants ,030104 developmental biology ,chemistry ,030211 gastroenterology & hepatology ,Nutraceutical ,Steatosis - Abstract
Liver diseases affect millions of people worldwide. In most of the cases, severe hepatic dysfunction and liver cancer stem from mild and common clinical signs including hepatic steatosis, insulin resistance, liver inflammation, and oxidative stress, all together referred to as Nonalcoholic Fatty Liver Disease (NAFLD). Nutraceuticals endowed with antioxidant activity have been shown to reduce NAFLD risk factors and exert hepatoprotective effects. Here, we test the protective effect exerted on liver by the antioxidant Taurisolo, a nutraceutical formulation produced by grape pomace and enriched in Resveratrol and Polyphenols. We analyze the effect of Taurisolo on liver cells by profiling the metabolome of in vitro cultured hepatic HuH7 cells and of C57BL-6J mice fed a High Fat Diet and treated with the nutraceutical. Both in vitro and in vivo, we provide evidence that Taurisolo reduces risk factor markers associated with NAFLD. Taurisolo stimulates glucose uptake and reduces hepatic cholesterol and serum triglycerides. Furthermore, we give new insights into the mechanism of action of Taurisolo. The nutraceutical increases mitochondrial activity and promotes respiration and ATP production, fostering catabolic reactions like fatty acid &beta, oxidation and amino acid catabolism. On the contrary, Taurisolo reduces anabolic reactions like biosynthesis of cholesterol, bile acids, and plasma membrane lipids.
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- 2020
35. Metabolic Effects of the Intracellular Regulation of Thyroid Hormone: Old Players, New Concepts
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Monica Dentice, Annunziata Gaetana Cicatiello, Daniela Di Girolamo, Cicatiello, Ag, Di Girolamo, D, and Dentice, M
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Deiodinase ,030209 endocrinology & metabolism ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,energy metabolism ,medicine ,Lipolysis ,Thyroid hormone receptor ,Deiodinases ,lcsh:RC648-665 ,biology ,Chemistry ,Thyroid ,Metabolism ,Thyroid hormone receptors ,Thyroid hormone ,local regulation of thyroid function ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Gluconeogenesis ,Iodothyronine deiodinase ,biology.protein ,Hormone - Abstract
Thyroid hormones (THs) are key determinants of cellular metabolism and regulate a variety of pathways that are involved in the metabolism of carbohydrates, lipids and proteins in several target tissues. Notably, hyperthyroidism induces a hyper-metabolic state characterized by increased resting energy expenditure, reduced cholesterol levels, increased lipolysis and gluconeogenesis followed by weight loss, whereas hypothyroidism induces a hypo-metabolic state characterized by reduced energy expenditure, increased cholesterol levels, reduced lipolysis and gluconeogenesis followed by weight gain. Thyroid hormone is also a key regulator of mitochondria respiration and biogenesis. Besides mirroring systemic TH concentrations, the intracellular availability of TH is potently regulated in target cells by a mechanism of activation/inactivation catalyzed by three seleno-proteins: type 1 and type 2 iodothyronine deiodinase (D1 and D2) that convert the biologically inactive precursor thyroxine T4 into T3, and type 3 iodothyronine deiodinase (D3) that inactivates TH action. Thus, the pleiotropic effects of TH can fluctuate among tissues and strictly depend on the cell-autonomous action of the deiodinases. Here we review the mechanisms of TH action that mediate metabolic regulation. This review traces the critical impact of peripheral regulation of TH by the deiodinases on the pathways that regulate energy metabolism and the balance among energy intake, expenditure and storage in specific target tissues.
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- 2018
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36. Hedgehog-mediated regulation of thyroid hormone action through iodothyronine deiodinases
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Monica Dentice and Dentice, M.
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deiodinase ,Thyroid Hormones ,Clinical Biochemistry ,Deiodinase ,Biology ,Iodide Peroxidase ,sonic hedgehog ,Mice ,Drug Discovery ,medicine ,Animals ,Humans ,Hedgehog Proteins ,Sonic hedgehog ,Hedgehog ,Cell proliferation ,Pharmacology ,Animal ,Cell growth ,Thyroid ,Embryogenesis ,Metamorphosis, Biological ,thyroid hormone ,Thyroxine ,Metabolic pathway ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,Triiodothyronine ,Molecular Medicine ,Hedgehog Protein ,Human ,Signal Transduction ,Hormone - Abstract
The three iodothyronine deiodinases catalyze the metabolic pathway that removes one iodine residue from the T4 molecule, thus producing either the active T3 or the inactive metabolite rT3. Hence, deiodination is a potent mechanism by which to modulate thyroid hormone (TH) action at cellular level, thereby allowing cells to customize their own T3 availability, both spatially and temporally, irrespective of TH serum concentrations. Sonic hedgehog (Hh) regulates patterning and growth of a remarkable variety of tissues throughout embryogenesis. Its constitutive activation is associated with cancer development.Recent evidences from two independent systems implicate the Hh signaling pathway in regulation of TH action via modulation of deiodinase expression. Interestingly, many critical developmental events, for example, amphibian metamorphosis, are tightly regulated by the TH and Hh signaling pathways. This review provides an overview of recent data referring to the intricate regulation of deiodinase activity and intracellular TH action by the Hh pathway.This functional cross-talk provides a paradigm for interaction between two key signaling pathways critical during development and neoplastic transformation. This interaction may be relevant in other tissues and situations in which the two signaling pathways participate. Deciphering these mechanisms constitutes an exciting field for future research.
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- 2011
37. Metabolic Instability of Type 2 Deiodinase Is Transferable To Stable Proteins Independently of Subcellular Localization
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Balázs Gereben, Monica Dentice, Anikó Zeöld, Antonio C. Bianco, John W. Harney, Cyntia Curcio-Morelli, Lívia Pormüller, Susana M. Tente, Zeold, A., Pormuller, L., Dentice, M., Harney, J. W., Curcio-Morelli, C., Tente, S. M., Bianco, A. C., and Gereben, B.
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Glycosylation ,Protein Conformation ,Deiodinase ,Molecular Sequence Data ,Membrane Transport Protein ,Endoplasmic Reticulum ,Iodide Peroxidase ,Biochemistry ,Protein structure ,Ubiquitin ,SEC62 ,Catalytic Domain ,Humans ,Amino Acid Sequence ,Molecular Biology ,biology ,Symporters ,Endoplasmic reticulum ,Cell Membrane ,Membrane Transport Proteins ,Cell Biology ,Subcellular localization ,Cell biology ,Protein Structure, Tertiary ,Protein destabilization ,Symporter ,Mutation ,biology.protein ,Human - Abstract
Thyroid hormone activation is catalyzed by two deiodinases, D1 and D2. Whereas D1 is a stable plasma membrane protein, D2 is resident in the endoplasmic reticulum (ER) and has a 20-min half-life due to selective ubiquitination and proteasomal degradation. Here we have shown that stable retention explains D2 residency in the ER, a mechanism that is nevertheless over-ridden by fusion to the long-lived plasma membrane protein, sodium-iodine symporter. Fusion to D2, but not D1, dramatically shortened sodium-iodine symporter half-life through a mechanism dependent on an 18-amino acid D2-specific instability loop. Similarly, the D2-specific loop-mediated protein destabilization was also observed after D2, but not D1, was fused to the stable ER resident protein SEC62. This indicates that the instability loop in D2, but not its subcellular localization, is the key determinant of D2 susceptibility to ubiquitination and rapid turnover rate. Our data also show that the 6 N-terminal amino acids, but not the 12 C-terminal ones, are the ones required for D2 recognition by WSB-1.
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- 2006
38. Intracellular Inactivation of Thyroid Hormone Is a Survival Mechanism for Muscle Stem Cell Proliferation and Lineage Progression
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Silvia Brunelli, Annamaria Colao, Gabriella Minchiotti, Luigi Del Vecchio, Cristina Luongo, Alessandro Marsili, Paola Zordan, Raffaele Ambrosio, Valentina Damiano, Domenico Salvatore, Siham Yennek, P. Reed Larsen, Monica Dentice, Shahragim Tajbakhsh, Ombretta Guardiola, Annarita Sibilio, Dentice, M, Ambrosio, R, Damiano, V, Sibilio, A, Luongo, C, Guardiola, O, Yennek, S, Zordan, P, Minchiotti, G, Colao, A, Marsili, A, Brunelli, S, Del Vecchio, L, Larsen, P, Tajbakhsh, S, Salvatore, D, Dentice, Monica, Colao, Annamaria, DEL VECCHIO, Luigi, Larsen, Pr, and Salvatore, Domenico
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Male ,Thyroid Hormones ,medicine.medical_specialty ,Satellite Cells, Skeletal Muscle ,Physiology ,muscle regeneration, thyroid hormone ,Deiodinase ,Apoptosis ,030209 endocrinology & metabolism ,MyoD ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Muscle, Skeletal ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,biology ,Cell growth ,Stem Cells ,Forkhead Box Protein O3 ,Thyroid ,BIO/13 - BIOLOGIA APPLICATA ,Skeletal muscle ,Forkhead Transcription Factors ,Cell Biology ,BIO/11 - BIOLOGIA MOLECOLARE ,Immunohistochemistry ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,biology.protein ,FOXO3 ,Stem cell ,Intracellular ,Signal Transduction - Abstract
Summary Precise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as acute skeletal muscle injury, type 3 deiodinase (D3), the thyroid hormone-inactivating enzyme, is induced in satellite cells where it reduces intracellular thyroid signaling. Satellite cell-specific genetic ablation of dio3 severely impairs skeletal muscle regeneration. This impairment is due to massive satellite cell apoptosis caused by exposure of activated satellite cells to the circulating TH. The execution of this proapoptotic program requires an intact FoxO3/MyoD axis, both genes positively regulated by intracellular TH. Thus, D3 is dynamically exploited in vivo to chronically attenuate TH signaling under basal conditions while also being available to acutely increase gene programs required for satellite cell lineage progression., Graphical Abstract, Highlights • D3 is induced in proliferating satellite cells thereby reducing thyroid signaling • D3 depletion causes massive cell apoptosis in vitro and in vivo • Apoptosis requires FoxO3, a TH target gene • Satellite cells customize TH signature and adapt it to their functional needs, Deiodinases inactivate thyroid hormone (TH) signaling, allowing a precise control of TH action at the cellular level. Dentice et al. find that type 3 deiodinase acts as a survival factor during skeletal muscle repair, and attenuation of TH signaling is required to prevent muscle stem cell apoptosis and promote lineage progression in vivo.
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- 2014
39. Mice with hepatocyte-specific deficiency of type 3 deiodinase have intact liver regeneration and accelerated recovery from nonthyroidal illness after toxin-induced hepatonecrosis
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Lai Ding, Jennifer S. Lee, Huai-Dong Song, Nicholas Y. Lee, Christina E. Hartigan, Chinweike Ukomadu, Kristen R. Vella, Valeriy Demchev, Roderick T. Bronson, Luciana A. Castroneves, Roy W A Peake, Mark D. Kellogg, Cuicui Guo, Rebecca H. Jugo, Henry A. Feldman, Agoston T. Agoston, Cristina Luongo, Michelle A. Maynard, Anal Desai, David M. Dorfman, Domenico Salvatore, Monica Dentice, Ari J. Wassner, Stephen A. Huang, Castroneves, La, Jugo, Rh, Maynard, Ma, Lee, J, Wassner, Aj, Dorfman, D, Bronson, Rt, Ukomadu, C, Agoston, At, Ding, L, Luongo, C, Guo, C, Song, H, Demchev, V, Lee, Ny, Feldman, Ha, Vella, Kr, Peake, Rw, Hartigan, C, Kellogg, Md, Desai, A, Salvatore, Domenico, Dentice, M, and Huang, Sa.
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Male ,medicine.medical_specialty ,Necrosis ,Deiodinase ,Iodide Peroxidase ,Mice ,Endocrinology ,Internal medicine ,medicine ,Animals ,Thyroid-TRH-TSH ,Carbon Tetrachloride ,Toxins, Biological ,Mice, Knockout ,Triiodothyronine ,biology ,Regeneration (biology) ,Low T3 Syndrome ,Recovery of Function ,Liver regeneration ,Liver Regeneration ,medicine.anatomical_structure ,Liver ,Organ Specificity ,Hypothyroxinemia ,Hepatocyte ,Hepatocytes ,biology.protein ,Female ,Chemical and Drug Induced Liver Injury ,medicine.symptom - Abstract
Type 3 deiodinase (D3), the physiologic inactivator of thyroid hormones, is induced during tissue injury and regeneration. This has led to the hypotheses that D3 impacts injury tolerance by reducing local T3 signaling and contributes to the fall in serum triiodothyronine (T3) observed in up to 75% of sick patients (termed the low T3 syndrome). Here we show that a novel mutant mouse with hepatocyte-specific D3 deficiency has normal local responses to toxin-induced hepatonecrosis, including normal degrees of tissue necrosis and intact regeneration, but accelerated systemic recovery from illness-induced hypothyroxinemia and hypotriiodothyroninemia, demonstrating that peripheral D3 expression is a key modulator of the low T3 syndrome.
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- 2014
40. UBIQUITINATION-INDUCED CONFORMATIONAL CHANGE WITHIN THE DEIODINASE DIMER IS A SWITCH REGULATING ENZYME ACTIVITY
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D. Vivek Sagar, G., Gereben, Balázs, Callebaut, Isabelle, Mornon, Jean-Paul, Zeöld, Anikó, S. da Silva, Wagner, Luongo, Cristina, Dentice, Monica, M. Tente, Susana, Beatriz, C., Freitas, G., W. Harney, John, Marie Zavacki, Ann, C. Bianco, Antonio, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Harvard Medical School [Boston] (HMS), Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine [Budapest] (KOKI), Hungarian Academy of Sciences (MTA)-Hungarian Academy of Sciences (MTA), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Sagar, G. D. V., Gereben, B., Callebaut, I., Mornon, J. -P., Zeold, A., Da Silva, W. S., Luongo, C., Dentice, M., Tente, S. M., Freitas, B. C. G., Harney, J. W., Zavacki, A. M., and Bianco, A. C.
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Models, Molecular ,Conformational change ,Molecular Sequence Data ,030209 endocrinology & metabolism ,Ubiquitin-conjugating enzyme ,Iodide Peroxidase ,Catalysis ,Protein Structure, Secondary ,Catalysi ,Cell Line ,Deubiquitinating enzyme ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,Ubiquitin ,Catalytic Domain ,Animals ,Humans ,Amino Acid Sequence ,Enzyme Reactivation ,Protein Structure, Quaternary ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,Animal ,Articles ,Cell Biology ,Transmembrane protein ,Protein Structure, Tertiary ,Cell biology ,Ubiquitin ligase ,Holoenzyme ,Biochemistry ,biology.protein ,Holoenzymes ,Dimerization ,Human ,Protein Binding ,Deubiquitination - Abstract
International audience; Ubiquitination is a critical posttranslational regulator of protein stability and/or subcellular localization. Here we show that ubiquitination can also regulate proteins by transiently inactivating enzymatic function through conformational change in a dimeric enzyme, which can be reversed upon de-ubiquitination. Our model system is the thyroid hormone activating type 2 deiodinase (D2), an endoplasmic reticulum resident type 1 integral membrane enzyme. D2 exists as a homodimer maintained by interacting surfaces at its transmembrane and globular cytosolic domains. The D2 dimer associates with the Hedgehog-inducible ubiquitin ligase WSB-1, the ubiquitin conjugase UBC-7, and VDU-1, a D2-specific deubiquitinase. Upon binding of T4, its natural substrate, D2 is ubiquitinated, which inactivates the enzyme by interfering with D2's globular interacting surfaces that are critical for dimerization and catalytic activity. This state of transient inactivity and change in dimer conformation persists until de-ubiquitination. The continuous association of D2 with this regulatory protein complex supports rapid cycles of deiodination, conjugation to ubiquitin, and enzyme reactivation by de-ubiquitination, allowing tight control of thyroid hormone action.
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- 2007
41. The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate
- Author
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Marcelo A. Christoffolete, Ann Marie Zavacki, Balázs Gereben, Cyntia Curcio-Morelli, Clifford J. Tabin, Brian W. Kim, Isabelle Callebaut, Anikó Zeöld, Sahar Nissim, John W. Harney, Monica Dentice, Luciane P. Capelo, Antonio C. Bianco, Amitabha Bandyopadhyay, Jean-Paul Mornon, Rogerio S. Ribeiro, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Harvard Medical School [Boston] (HMS), Department of Genetics [Boston], Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine [Budapest] (KOKI), Hungarian Academy of Sciences (MTA)-Hungarian Academy of Sciences (MTA), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Dentice, M., Bandyopadhyay, A., Gereben, B., Callebaut, I., Christoffolete, M. A., Kim, B. W., Nissim, S., Mornon, J. -P., Zavacki, A. M., Zeold, A., Capelo, L. P., Curcio-Morelli, C., Ribeiro, R., Harney, J. W., Tabin, C. J., Bianco, A. C., and Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Models, Molecular ,Ubiquitin-Protein Ligase ,Beta-Transducin Repeat-Containing Proteins ,Transcription Factor ,Cellular differentiation ,Elongin ,Gene Expression ,Chick Embryo ,Two-Hybrid System Technique ,Mice ,0302 clinical medicine ,Ubiquitin ,Thyroid Hormone ,Growth Plate ,Protein Subunit ,In Situ Hybridization ,0303 health sciences ,biology ,Cell Differentiation ,3. Good health ,Cell biology ,Ubiquitin ligase ,Trans-Activator ,030220 oncology & carcinogenesis ,RNA Interference ,Hedgehog Protein ,Human ,Protein Binding ,Molecular Sequence Data ,Transfection ,Iodide Peroxidase ,Models, Biological ,03 medical and health sciences ,Immunoprecipitation ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Amino Acid Sequence ,Transcription factor ,Hedgehog ,030304 developmental biology ,Parathyroid hormone-related protein ,Sequence Homology, Amino Acid ,Tibia ,Animal ,Protein ,Binding Site ,Parathyroid Hormone-Related Protein ,Cell Biology ,Chondrocyte ,beta-Transducin Repeat-Containing Proteins ,Molecular biology ,Iodothyronine deiodinase ,Mutation ,biology.protein - Abstract
WSB-1 is a SOCS-box-containing WD-40 protein of unknown function that is induced by Hedgehog signalling in embryonic structures during chicken development. Here we show that WSB-1 is part of an E3 ubiquitin ligase for the thyroid-hormone-activating type 2 iodothyronine deiodinase (D2). The WD-40 propeller of WSB-1 recognizes an 18-amino-acid loop in D2 that confers metabolic instability, whereas the SOCS-box domain mediates its interaction with a ubiquitinating catalytic core complex, modelled as Elongin BC-Cul5-Rbx1 (ECS(WSB-1)). In the developing tibial growth plate, Hedgehog-stimulated D2 ubiquitination via ECS(WSB-1) induces parathyroid hormone-related peptide (PTHrP), thereby regulating chondrocyte differentiation. Thus, ECS(WSB-1) mediates a mechanism by which 'systemic' thyroid hormone can effect local control of the Hedgehog-PTHrP negative feedback loop and thus skeletogenesis.
- Published
- 2006
42. Pendrin is a Novel In Vivo Downstream Target Gene of the TTF-1/Nkx-2.1 Homeodomain Transcription Factor in Differentiated Thyroid Cells
- Author
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Salvatore Salzano, Domenico Salvatore, Guido Rossi, Gianfranco Fenzi, Roberto Di Lauro, Mariastella Zannini, Raffaele Ambrosio, Roberto Nitsch, Cristina Luongo, Monica Dentice, Antonia Elefante, Dentice, M, Luongo, C., Elefante, A., Ambrosio, R., Salzano, S., Zannini, M., Nitsch, R., DI LAURO, R., Rossi, G., Fenzi, G., and Salvatore, D.
- Subjects
endocrine system diseases ,medicine.medical_treatment ,EMX2 ,Thyroid Nuclear Factor 1 ,Oligonucleotides ,Thyroid Gland ,Gene Expression ,Protein Isoforms ,Chloride-Bicarbonate Antiporters ,Genes, Dominant ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Thyroid ,Nuclear Proteins ,Cell Differentiation ,respiratory system ,Chromatin ,medicine.anatomical_structure ,Sulfate Transporters ,RNA Interference ,Plasmids ,Protein Binding ,Gene isoform ,endocrine system ,Chromatin Immunoprecipitation ,Blotting, Western ,Molecular Sequence Data ,Down-Regulation ,Transfection ,medicine ,Animals ,Humans ,Immunoprecipitation ,RNA, Messenger ,Thyroid Neoplasms ,Molecular Biology ,Ions ,Thyroid hormone receptor ,Binding Sites ,Base Sequence ,Membrane Transport Proteins ,Promoter ,Cell Biology ,Pendrin ,DNA ,Blotting, Northern ,Molecular biology ,Introns ,Protein Structure, Tertiary ,Rats ,Gene Expression Regulation ,biology.protein ,Thyroglobulin ,PAX8 ,HeLa Cells ,Transcription Factors - Abstract
Thyroid transcription factor gene 1 (TTF-1) is a homeobox-containing gene involved in thyroid organogenesis. During early thyroid development, the homeobox gene Nkx-2.5 is expressed in thyroid precursor cells coincident with the appearance of TTF-1. The aim of this study was to investigate the molecular mechanisms underlying thyroid-specific gene expression. We show that the Nkx-2.5 C terminus interacts with the TTF-1 homeodomain and, moreover, that the expression of a dominant-negative Nkx-2.5 isoform (N188K) in thyroid cells reduces TTF-1-driven transcription by titrating TTF-1 away from its target DNA. This process reduced the expression of several thyroid-specific genes, including pendrin and thyroglobulin. Similarly, down-regulation of TTF-1 by RNA interference reduced the expression of both genes, whose promoters are sensitive to and directly associate with TTF-1 in the chromatin context. In conclusion, we demonstrate that pendrin and thyroglobulin are downstream targets in vivo of TTF-1, whose action is a prime factor in controlling thyroid differentiation in vivo.
- Published
- 2005
43. Endoplasmic reticulum-associated degradation of the human type 2 iodothyronine deiodinase (D2) is mediated via an association between mammalian UBC7 and the carboxyl region of D2
- Author
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P. Reed Larsen, Antonio C. Bianco, Monica Dentice, John W. Harney, Cyntia Curcio-Morelli, Ann Marie Zavacki, Brian W. Kim, Kim, B. W., Zavacki, A. M., Curcio-Morelli, C., Dentice, M., Harney, J. W., Larsen, P. R., and Bianco, A. C.
- Subjects
Endoplasmic-reticulum-associated protein degradation ,Endoplasmic Reticulum ,Iodide Peroxidase ,Endoplasmic Reticulum Degradation Pathway ,Endocrinology ,Ubiquitin ,Humans ,Cloning, Molecular ,Cycloheximide ,Molecular Biology ,Kinetic ,chemistry.chemical_classification ,Binding Sites ,biology ,Endoplasmic reticulum ,Binding Site ,General Medicine ,Recombinant Protein ,Fusion protein ,Recombinant Proteins ,Amino acid ,Kinetics ,Thyroxine ,chemistry ,Biochemistry ,Iodothyronine deiodinase ,Ubiquitin-Conjugating Enzymes ,biology.protein ,Triiodothyronine ,Selenoprotein ,Human - Abstract
The type 2 iodothyronine selenodeiodinase (D2) is an endoplasmic reticulum (ER)-resident selenoprotein that activates T4 to T3, playing a critical role in thyroid homeostasis. D2 has an approximately 45-min half-life due to selective ubiquitin-mediated ER-associated degradation (ERAD), a process of particular interest because it is accelerated by exposure to D2 substrates, T4 or rT3. The present in vitro binding studies indicate that glutathione-S-transferase (GST)-human D2 fusion proteins specifically associate with a mammalian homolog of the ubiquitin conjugase UBC7 (MmUBC7), with localization to amino acids 169-234 of D2. Coexpression of D2 with an inactive D2 mutant or a truncated version containing amino acids 169-234 stabilizes D2 half-life, supporting the importance of the carboxyl region of D2 for ERAD. Mammalian UBC6 (MmUBC6) does not directly associate with D2 but can associate with a complex containing UBC7 and D2. At the same time, functional studies in human embryonic kidney-293 cells indicate that D2 activity half-life and protein levels are stabilized only when inactive mutants of both UBC6 and UBC7 are overexpressed with D2, suggesting that redundancy may exist at the level of the E2 for both basal and substrate-accelerated D2 ERAD. In conclusion, D2 ERAD in human cells proceeds via an association between UBC7 and the carboxyl region of D2, a unique mechanism for the control of thyroid hormone activation.
- Published
- 2003
44. ASPETTI ENERGETICI AMBIENTALI ED ECONOMICI DEL CICLO INTEGRATO DEI RIFIUTI URBANI
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DENTICE D'ACCADIA, MASSIMO, VANOLI, RAFFAELE, L. VANOLI, Vanoli, Raffaele, Vanoli, L., Dentice, M., DENTICE D'ACCADIA, Massimo, and L., Vanoli
- Published
- 2002
45. Studio di fattibilità e convenienza economica della cogenerazione al servizio degli impianti di climatizzazione
- Author
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M. Dentice d'Accadia, R. Vanoli, SIBILIO, Sergio, DENTICE D'ACCADIA, Massimo, Sibilio, S., Vanoli, R., Vanoli, Raffaele, Dentice, M., Sibilio, M., M., Dentice d'Accadia, R., Vanoli, and Sibilio, Sergio
- Published
- 1998
46. The key roles of thyroid hormone in mitochondrial regulation, at interface of human health and disease.
- Author
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Sagliocchi S, Restolfer F, Cossidente A, and Dentice M
- Abstract
Mitochondria are highly plastic and dynamic organelles long known as the powerhouse of cellular bioenergetics, but also endowed with a critical role in stress responses and homeostasis maintenance, supporting and integrating activities across multifaced cellular processes. As a such, mitochondria dysfunctions are leading causes of a wide range of diseases and pathologies. Thyroid hormones (THs) are endocrine regulators of cellular metabolism, regulating intracellular nutrients fueling of sugars, amino acids and fatty acids. For instance, THs regulate the balance between the anabolism and catabolism of all the macro-molecules, influencing energy homeostasis during different nutritional conditions. Noteworthy, not only most of the TH-dependent metabolic modulations act via the mitochondria, but also THs have been proved to regulate the mitochondrial biosynthesis, dynamics and function. The significance of such an interplay is different in the context of specific tissues and strongly impacts on cellular homeostasis. Thus, a comprehensive understanding of THs-dependent mitochondrial functions and dynamics is required to develop more precise strategies for targeting mitochondrial function. Herein, we describe the mechanisms of TH-dependent metabolic regulation with a focus on mitochondrial action, in different tissue contexts, thus providing new insights for targeted modulation of mitochondrial dynamics., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)
- Published
- 2024
- Full Text
- View/download PDF
47. The histone methyltransferase SMYD1 is induced by thermogenic stimuli in adipose tissue.
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Cicatiello AG, Nappi A, Franchini F, Nettore IC, Raia M, Rocca C, Angelone T, Dentice M, Ungaro P, and Macchia PE
- Subjects
- Animals, Mice, 3T3-L1 Cells, Histone Methyltransferases, Mice, Inbred C57BL, Adipose Tissue, Thermogenesis genetics
- Abstract
Aim: To study the expression of histone methyltransferase SMYD1 in white adipose tissue (WAT) and brown adipose tissue and during differentiation of preadipocytes to white and beige phenotypes. Methods: C57BL/6J mice fed a high-fat diet (and exposed to cold) and 3T3-L1 cells stimulated to differentiate into white and beige adipocytes were used. Results: SMYD1 expression increased in WAT of high-fat diet fed mice and in WAT and brown adipose tissue of cold-exposed mice, suggesting its role in thermogenesis. SMYD1 expression was higher in beige adipocytes than in white adipocytes, and its silencing leads to a decrease in mitochondrial content and in Pgc-1α expression. Conclusion: These data suggest a novel role for SMYD1 as a positive regulator of energy control in adipose tissue.
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- 2024
- Full Text
- View/download PDF
48. Therapeutic Effect of an Ursolic Acid-Based Nutraceutical on Neuronal Regeneration after Sciatic Nerve Injury.
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Iannuzzo F, Cicatiello AG, Sagliocchi S, Schiano E, Nappi A, Miro C, Stornaiuolo M, Mollica A, Tenore GC, Dentice M, and Novellino E
- Subjects
- Animals, Mice, Ursolic Acid, Sciatic Nerve, Dietary Supplements, Muscle Fibers, Skeletal, Peripheral Nerve Injuries drug therapy
- Abstract
Peripheral nerve injuries lead to severe functional impairments and long recovery times, with limited effectiveness and accessibility of current treatments. This has increased interest in natural bioactive compounds, such as ursolic acid (UA). Our study evaluated the effect of an oleolyte rich in UA from white grape pomace (WGPO) on neuronal regeneration in mice with induced sciatic nerve resection, administered concurrently with the induced damage (the WGPO group) and 10 days prior (the PRE-WGPO group). The experiment was monitored at two-time points (4 and 10 days) after injury. After 10 days, the WGPO group demonstrated a reduction in muscle atrophy, evidenced by an increased number and diameter of muscle fibers and a decreased Atrogin-1 and Murf-1 expression relative to the denervated control. It was also observed that 85.7% of neuromuscular junctions (NMJs) were fully innervated, as indicated by the colocalization of α-bungarotoxin and synaptophysin, along with the significant modulation of Oct-6 and S-100. The PRE-WGPO group showed a more beneficial effect on nerve fiber reformation, with a significant increase in myelin protein zero and 95.2% fully innervated NMJs, and a pro-hypertrophic effect in resting non-denervated muscles. Our findings suggest WGPO as a potential treatment for various conditions that require the repair of nerve and muscle injuries.
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- 2024
- Full Text
- View/download PDF
49. SIRT6 pharmacological inhibition delays skin cancer progression in the squamous cell carcinoma.
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Abbotto E, Miro C, Piacente F, Salis A, Murolo M, Nappi A, Millo E, Russo E, Cichero E, Sturla L, Del Rio A, De Flora A, Nencioni A, Dentice M, and Bruzzone S
- Subjects
- Animals, Mice, Keratin-8, Vimentin, Keratin-6, Carcinogenesis, Skin Neoplasms drug therapy, Carcinoma, Squamous Cell drug therapy, Papilloma, Sirtuins
- Abstract
Sirtuin 6 (SIRT6) has a critical role in cutaneous Squamous Cell Carcinoma (cSCC): SIRT6 silencing in skin SCC cells has pro-differentiating effects and SIRT6 deletion abrogated DMBA-TPA-induced skin tumorigenesis in mice. On the other hand, SIRT6 acts as tumor suppressor in SCC by enhancing glycolysis in tumor propagating cells. Herein, pharmacological modulation of SIRT6 deacetylase activity was investigated in cSCC, with S6 (inhibitor) or MDL-800 (activator). In cSCC cells, S6 recreated the pro-differentiating effects of SIRT6 silencing, as the levels of Keratin 1, Keratin 10 and Loricrin were upregulated compared to controls. Next, the effects of SIRT6 pharmacological modulation were evaluated in a DMBA-TPA-induced skin cancer mouse model. Mice treated with the inhibitor S6 in a preventive approach, i.e. at the beginning of the promotion stage, presented reduced number and size of papillomas, compared to the controls. The epidermal hyperproliferation marker Keratin 6 and the cSCC marker Keratin 8 were less abundant when SIRT6 was inhibited. In S6-treated lesions, the Epithelial-Mesenchymal Transition (EMT) markers Zeb1 and Vimentin were less expressed compared to untreated lesions. In a therapeutic approach, i.e. treatment starting after papilloma appearance, the S6 group presented reduced papillomas (number and size), whereas MDL-800-treated mice displayed an opposite trend. In S6-treated lesions, Keratin 6 and Keratin 8 were less expressed, EMT was less advanced, with a higher E-cadherin/Vimentin ratio, indicating a delayed carcinogenesis when SIRT6 was inhibited. Our results confirm that SIRT6 plays a role in skin carcinogenesis and suggest SIRT6 pharmacological inhibition as a promising strategy in cSCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2023
- Full Text
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50. Thyroid Hormone Regulates the Lipid Content of Muscle Fibers, Thus Affecting Physical Exercise Performance.
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Miro C, Nappi A, Sagliocchi S, Di Cicco E, Murolo M, Torabinejad S, Acampora L, Pastore A, Luciano P, La Civita E, Terracciano D, Stornaiuolo M, Dentice M, and Cicatiello AG
- Subjects
- Thyroid Hormones metabolism, Exercise, Fatty Acids metabolism, Muscle Fibers, Skeletal metabolism, Muscle, Skeletal metabolism
- Abstract
Skeletal muscle (SkM) lipid composition plays an essential role in physiological muscle maintenance and exercise performance. Thyroid hormones (THs) regulate muscle formation and fuel energy utilization by modulating carbohydrates and lipid and protein metabolism. The best-known effects of THs in SkM include the promotion of mitochondrial biogenesis, the fiber-type switch from oxidative to glycolytic fibers, and enhanced angiogenesis. To assess the role of THs on the lipidic composition of SkM fibers, we performed lipidomic analyses of SkM cells and tissues, glucose tolerance experiments, and exercise performance tests. Our data demonstrated that TH treatment induces remodeling of the lipid profile and changes the proportion of fatty acids in SkM. In brief, THs significantly reduced the ratio of stearic/oleic acid in the muscle similar to what is induced by physical activity. The increased proportion of unsaturated fatty acids was linked to an improvement in insulin sensitivity and endurance exercise. These findings point to THs as critical endocrine factors affecting exercise performance and indicate that homeostatic maintenance of TH signals, by improving cell permeability and receptor stability at the cell membrane, is crucial for muscle physiology.
- Published
- 2023
- Full Text
- View/download PDF
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