145 results on '"Pedersen JZ"'
Search Results
2. Thyroid hormones inhibit cell migration and proliferation activated by IGF-1 and MCP-1 in THP-1 monocytes through integrin αvβ3 by different mechanisms
- Author
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Candelotti, E, De Luca, R, Megna, R, Maiolo, M, De Vito, P, Percario, Z, Borgatti, M, Gambari, R, Davis, Pj, Lin, Hy, Polticelli, F, Persichini, T, Colasanti, M, Affabris, E, Pedersen, Jz, and Incerpi, S
- Subjects
MCP-1 induced proliferation ,Thyroid hormones and IGF-1 Cross-talk ,Thyroid hormones ,Nongenomic effects ,Integrin αvβ3 ,Settore BIO/10 - Published
- 2021
3. Antiviral thiazolides inhibit paramyxovirus replication by targeting the Fusion protein folding: role of glycoprotein-specific disulfide isomerase ERp57
- Author
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La Frazia, S, Piacentini, S, Riccio, A, Pedersen, Jz, Nicolotti, O, Rossignol, J, and Santoro, Mg
- Subjects
Settore MED/07 - Published
- 2018
4. Nitazoxanide inhibits paramyxovirus replication by targeting the Fusion protein folding: role of glycoprotein-specific thiol oxidoreductase ERp57
- Author
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Piacentini, S, La Frazia, S, Riccio, A, Pedersen, J, Topai, A, Nicolotti, O, Rossignol, J, Santoro, M, and Pedersen, Jz
- Subjects
0301 basic medicine ,Protein Folding ,Paramyxoviridae ,viruses ,Protein Disulfide-Isomerases ,lcsh:Medicine ,Virus Replication ,Virus ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Viral envelope ,medicine ,Animals ,Humans ,lcsh:Science ,Multidisciplinary ,Binding Sites ,Paramyxoviridae Infections ,biology ,lcsh:R ,Nitazoxanide ,biology.organism_classification ,Settore MED/07 - Microbiologia e Microbiologia Clinica ,Nitro Compounds ,Virology ,Tizoxanide ,Fusion protein ,Sendai virus ,Protein Transport ,Thiazoles ,030104 developmental biology ,Targeted drug delivery ,chemistry ,A549 Cells ,lcsh:Q ,Oxidoreductases ,Viral Fusion Proteins ,medicine.drug - Abstract
Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There is no effective antiviral chemotherapy for most of these pathogens. Paramyxoviruses evolved a sophisticated membrane-fusion machine consisting of receptor-binding proteins and the fusion F-protein, critical for virus infectivity. Herein we identify the antiprotozoal/antimicrobial nitazoxanide as a potential anti-paramyxovirus drug targeting the F-protein. We show that nitazoxanide and its circulating-metabolite tizoxanide act at post-entry level by provoking Sendai virus and RSV F-protein aggregate formation, halting F-trafficking to the host plasma membrane. F-protein folding depends on ER-resident glycoprotein-specific thiol-oxidoreductase ERp57 for correct disulfide-bond architecture. We found that tizoxanide behaves as an ERp57 non-competitive inhibitor; the putative drug binding-site was located at the ERp57-b/b′ non-catalytic domains interface. ERp57-silencing mimicked thiazolide-induced F-protein alterations, suggesting an important role of this foldase in thiazolides anti-paramyxovirus activity. Nitazoxanide is used in the clinic as a safe and effective antiprotozoal/antimicrobial drug; its antiviral activity was shown in patients infected with hepatitis-C virus, rotavirus and influenza viruses. Our results now suggest that nitazoxanide may be effective also against paramyxovirus infection.
- Published
- 2018
5. Thyroid hormones crosstalk with growth factors: old facts and new hypotheses
- Author
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CANDELOTTI, ELENA, INCERPI, Sandra, De Vito, P, Ahmed, RG, Luly, P, Davis, PJ, Pedersen, JZ, Candelotti, Elena, De Vito, P, Ahmed, Rg, Luly, P, Davis, Pj, Pedersen, Jz, and Incerpi, Sandra
- Abstract
Nongenomic effects of thyroid hormones typically start at the cell surface and do not primarily involve the classical nuclear receptors, but rather a plasma membrane receptor site identified about ten years ago on the integrin v3. Transduction of the thyroid hormone signal from this integrin receptor involves activation of the MAPK pathway and may lead to events such as angiogenesis or tumor cell proliferation. This review focuses on the interaction of thyroid hormones with growth factors, in fact the integrin v3 has been reported to a be a co-receptor for several growth factors such as EGF, IGF-1 and the FGF family, but also for small molecules like resveratrol. Binding of the ligand to integrin v3 is inhibited by tetrac, a metabolite of L-thyroxine, and by its nanoparticulate formulation nanotetrac. Recent microarray studies on tumor cells have shown that tetrac has antiinflammatory effects that are mediated by integrin v3, and tetrac can downregulate the expression of several interleukin genes. Crosstalk between thyroid hormones and vascular growth factors is important for cell migration, vascular calcification and the angiogenic process. Thyroid hormones also show pleiotropic effects on osteoblast function and differentiation, as well as in early pregnancy. The importance of thyroid hormone interaction with neurotrophins and interleukins has also been examined. With integrin v3 firmly established as the plasma membrane receptor future studies will focus on the crosstalk between thyroid hormones and growth factors in order to verify the efficiency of new pharmacological tools, such as nanotetrac.
- Published
- 2015
6. Thyroid hormone inhibition in L6 myoblasts of IGF-1-mediated glucose uptake and proliferation: new roles for integrin αvβ3
- Author
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INCERPI, Sandra, CANDELOTTI, ELENA, LEONE, STEFANO, Hsieh, M. T, Lin, H. Y, Cheng, G. Y, De Vito, P, Fiore, A. M, Ahmed, Rg, Salvia, R, Luly, P, Pedersen, Jz, Davis FB, B., Davis, Pj, Incerpi, Sandra, Hsieh, M. T, Lin, H. Y, Cheng, G. Y, De Vito, P, Fiore, A. M, Ahmed, Rg, Salvia, R, Candelotti, Elena, Leone, Stefano, Luly, P, Pedersen, Jz, Davis FB, B., and Davis, Pj
- Subjects
integrin alphavbeta3 ,Insulin -like growth factor -1 ,thyroid hormone - Abstract
Thyroid hormones L-thyroxine (T4) and 3,5,3’-triiodo-L-thyronine (T3) have been shown to initiate short- and long-term effects via a plasma membrane receptor site located on integrin vβ3. Also insulin-like growth factor-1 (IGF-1) activity is known to be subject to regulation by this integrin. To investigate the possible cross-talk between T4 and IGF-1 in rat L6 myoblasts, we have examined integrin αvβ3-mediated modulatory actions of T4 on glucose uptake, measured through carrier-mediated 2-deoxy-[3H]-D-glucose uptake, and on cell proliferation stimulated by IGF-1, assessed by cell counting, [3H]-thymidine incorporation and FACS analysis. IGF-1 stimulated glucose transport and cell proliferation via the cell surface IGF-1 receptor (IGF1R) and, downstream of the receptor, by the phosphatidylinositol 3-kinase signal transduction pathway. Addition of 0.1 nM free T4 caused little or no cell proliferation, but prevented both glucose uptake and proliferative actions of IGF1. These actions of T4 were mediated by an Arg-Gly-Asp (RGD)-sensitive pathway, suggesting the existence of crosstalk between IGF1R and the T4 receptor located near the RGD recognition site on the integrin. An RGD-sequence-containing integrin inhibitor, a monoclonal antibody to v3, and the T4 metabolite tetraiodothyroacetic acid all blocked the inhibition by T4 of IGF-1-stimulated glucose uptake and cell proliferation. Western blotting confirmed roles for activated phosphatidylinositol 3-kinase and extracellular regulated kinase 1/2 (ERK1/2) in the effects of IGF-1, and also showed a role for ERK1/2 in the actions of T4 that modified the effects of IGF-1. We conclude that thyroid hormone inhibits IGF-1-stimulated glucose uptake and cell proliferation in L6 myoblasts.
- Published
- 2014
7. 'Cross-talk between thyroid hormone and IGF-1 in THP-1 monocytes is mediated by integrin αvβ3'
- Author
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CANDELOTTI, ELENA, Salvia R, Leone S, De Vito P, Pedersen JZ, Luly P, Incerpi S., Candelotti, Elena, Salvia, R, Leone, S, De Vito, P, Pedersen, Jz, Luly, P, and Incerpi, S.
- Published
- 2013
8. The extreme hyper-reactivity of selected cysteines drives hierarchical disulfide bond formation in serum albumin.
- Author
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Bocedi, A, Fabrini, R, Pedersen, Jz, Federici, G, Iavarone, Federica, Martelli, Claudia, Castagnola, Massimo, Ricci, Giuseppe, Iavarone, Federica (ORCID:0000-0002-2074-5531), Castagnola, Massimo (ORCID:0000-0002-0959-7259), Bocedi, A, Fabrini, R, Pedersen, Jz, Federici, G, Iavarone, Federica, Martelli, Claudia, Castagnola, Massimo, Ricci, Giuseppe, Iavarone, Federica (ORCID:0000-0002-2074-5531), and Castagnola, Massimo (ORCID:0000-0002-0959-7259)
- Abstract
After mild reduction of serum albumin, seven among the 34 cysteines forming the disulfide network displayed a surprising hyper-reactivity. Compared to the thiol group of glutathione, the average reactivity of these cysteines towards disulfides and thiol reagents was more than 100 times higher. Using mass spectrometry and kinetic data, we identified all these unusual residues, with Cys75, Cys123 and Cys264 showing the highest reactivity. This effect was mainly due to a low pKa of the sulfhydryl groups and may explain the very fast formation of early disulfides in the nascent protein suggesting the existence of a hierarchical propensity to form such covalent links in selected regions during oxidative folding. An identical pattern of hyper-reactive cysteines was found in albumins from six different mammals. This hyper-reactivity is much higher than the one found in other proteins containing multiple cysteines only devoted to structural disulfide bonds. It is possible that such hyper-reactive cysteines could also be present in other proteins, although their existence has been completely ignored so far.
- Published
- 2016
9. Theoretical and experimental studies on the structure-antioxidant activity relationship of synthetic 4-methylcoumarins
- Author
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Barzegar A, Davari MD, Chaparzadeh N, Zarghami N, Pedersen JZ, LSaso L, Moosavi Movahedi AA, INCERPI, Sandra, Barzegar, A, Davari, Md, Chaparzadeh, N, Zarghami, N, Pedersen, Jz, Incerpi, Sandra, Lsaso, L, and Moosavi Movahedi, Aa
- Subjects
reactive oxygen specie ,antioxidant ,coumarin - Abstract
The development of antioxidants as useful drugs for the treatment of neurodegenerative diseases such as Alzheimer's is extremely challenging in medicinal chemistry. Coumarins have attracted great attention as possible therapeutic tools against oxygen radicals in human degenerative diseases. In order to establish the possible structure-antioxidant activity relationship, a series of twenty four 4-methylcoumarin derivatives were examined by employing reducing power measurements, and comparison with bond dissociation enthalpy and ionization potential calculations. Based on the reducing potency of 4-methylcoumarin derivatives with respect to trolox, these compounds were classified into five groups as “most active”, “more active”, “moderately active”, “less active” and “inactive” derivatives. The presence of hydroxyl groups is an essential requirement for the activity, and substitution of hydroxyl groups by methoxy groups leads to non-active derivatives. The results revealed that dihydroxyl groups in the ortho position show a better antioxidant activity with respect to dihydroxyl groups in the meta position. This is ascribed to the ability to construct more stable 4-methylcoumarin radical intermediates by rearrangement of intra-molecular hydrogen bonding. Our findings indicate that other important factors to enhance the antioxidant activity of coumarins are the number of hydroxyl groups, the presence of ester substitutions and a thiono functional group on the pyrone ring. However, bond dissociation enthalpy and ionization potential calculations alone are not sufficient to identify the best antioxidant structures. As a result, chemical and functional properties of molecules such as 4-methylcoumarins should be examined as a whole entity, considering all substitutions versus a single substitution to design functional compounds with good antioxidant activity.
- Published
- 2011
10. Extranuclear Effects of Thyroid Hormones in Skeletal Muscle
- Author
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INCERPI, Sandra, DE VITO P, PEDERSEN JZ AND LULY P., Incerpi, Sandra, DE VITO, P, and PEDERSEN JZ AND LULY, P.
- Published
- 2011
11. Electrostatic association of glutathione transferase to the nuclear membrane. Evidence of an enzyme defense barrier at the nuclear envelope
- Author
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Stella, L, Pallottini, V, Moreno, S, Leoni, S, De Maria, F, Turella, P, Federici, G, Fabrini, R, Dawood, K, LO BELLO, M, Pedersen, Jz, Ricci, G, Stella, L, Pallottini, Valentina, Moreno, Sandra, Leoni, S, De Maria, F, Turella, P, Federici, G, Fabrini, R, Dawood, Kf, Lo Bello, M, Pedersen, Jz, and Ricci, G.
- Subjects
Male ,Wistar ,metal complexes ,animal cell ,Wistar rat ,confocal microscopy ,immunology ,iron ,cell nucleus membrane ,enzyme kinetics ,rat ,animal ,electricity ,Settore CHIM/02 - Chimica Fisica ,Glutathione Transferase ,quantitative analysis ,Settore BIO/12 ,article ,liver cell ,cell line ,cells ,physiology ,cytosolic pools ,immunofluorescence ,isoenzymes ,nuclear fractions ,glutathione transferase ,glutathione transferase alpha ,liposome ,membrane enzyme ,glutathione S-transferase alpha ,glutathione transferase P1 ,Gstp1 protein, rat ,isoenzyme ,cell compartmentalization ,cell function ,cell nucleus ,cytosol ,DNA damage ,enzyme analysis ,enzyme localization ,human ,human cell ,male ,molecular model ,nonhuman ,priority journal ,protein assembly ,protein protein interaction ,chemistry ,enzymology ,metabolism ,protein binding ,tumor cell line ,rattus ,animals ,cell line, tumor ,electrostatics ,glutathione S-transferase pi ,hepatocytes ,humans ,nuclear envelope ,rats ,rats, Wistar ,Isoenzymes ,Protein Binding ,tumor ,Nuclear Envelope ,Static Electricity ,Cell Line, Tumor ,Animals ,Humans ,Gstp1 protein ,Settore BIO/10 ,Rats, Wistar ,Rats ,Glutathione S-Transferase pi ,Hepatocytes - Abstract
The possible nuclear compartmentalization of glutathione S-transferase (GST) isoenzymes has been the subject of contradictory reports. The discovery that the dinitrosyl-diglutathionyl- iron complex binds tightly to Alpha class GSTs in rat hepatocytes and that a significant part of the bound complex is also associated with the nuclear fraction (Pedersen, J. Z., De Maria, F., Turella, P., Federici, G., Mattei, M., Fabrini, R., Dawood, K. F., Massimi, M., Caccuri, A. M., and Ricci, G. (2007) J. Biol. Chem. 282, 6364–6371) prompted us to reconsider the nuclear localization of GSTs in these cells. Surprisingly, we found that a considerable amount of GSTs corresponding to 10% of the cytosolic pool is electrostatically associated with the outer nuclear membrane, and a similar quantity is compartmentalized inside the nucleus. Mainly Alpha class GSTs, in particular GSTA1-1, GSTA2-2, and GSTA3-3, are involved in this double modality of interaction. Confocal microscopy, immunofluorescence experiments, and molecular modeling have been used to detail the electrostatic association in hepatocytes and liposomes. A quantitative analysis of the membrane-bound Alpha GSTs suggests the existence of a multilayer assembly of these enzymes at the outer nuclear envelope that could represent an amazing novelty in cell physiology. The interception of potentially noxious compounds to prevent DNA damage could be the possible physiological role of the perinuclear and intranuclear localization of Alpha GSTs.
- Published
- 2007
12. Electrostatic association of glutathione transferase to the nuclear membrane: Evidence of a defense barrier at the nuclear envelope
- Author
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STELLA L, MORENO S, LEONI S, DE MARIA F, TURELLA P, FEDERICI, G, FABRINI R, DAWOOD KF, LO BELLO M, PEDERSEN JZ, RICCI G., PALLOTTINI, Valentina, Stella, L, Pallottini, Valentina, Moreno, S, Leoni, S, DE MARIA, F, Turella, P, Federici, G, Fabrini, R, Dawood, Kf, LO BELLO, M, Pedersen, Jz, and Ricci, G.
- Subjects
nuclear membrane ,glutatione tranferase ,electrostatic association - Abstract
The possible nuclear compartmentalization of glutathione transferase isoenzymes has been the subject of contradictory reports. The discovery that the dinitrosyl-diglutathionyl-iron complex binds tightly to Alpha class GSTs in rat hepatocytes and that a significant part of the bound complex is also associated to the nuclear fraction (Pedersen et al., the accompanying paper), prompted us to reconsider the nuclear localization of GSTs in these cells. Surprisingly, we found that a considerable amount of GSTs corresponding to 10% of the cytosolic pool, is electrostatically associated to the outer nuclear membrane, and a similar quantity is compartmentalized inside the nucleus. Mainly Alpha class GSTs, in particular GSTA1-1, GSTA2-2 and GSTA3-3 are involved in this double modality of interaction. Confocal microscopy, immunofluorescence experiments and molecular modeling have been used to detail the electrostatic association in hepatocytes and liposomes. A quantitative analysis of the membrane bound Alpha GSTs suggests the existence of a multilayer assembly of these enzymes at the outer nuclear envelope that could represent an amazing novelty in cell physiology. The interception of potentially noxious compounds to prevent DNA damage could be the possible physiological role of the perinuclear and intranuclear localization of Alpha GSTs.
- Published
- 2007
13. Erythrocyte glutathione transferase: a general probe for chemical contaminations in mammals
- Author
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Bocedi, A, primary, Fabrini, R, additional, Lai, O, additional, Alfieri, L, additional, Roncoroni, C, additional, Noce, A, additional, Pedersen, JZ, additional, and Ricci, G, additional
- Published
- 2016
- Full Text
- View/download PDF
14. The specific interaction of dinitrosyl-diglutathionyl-iron complex, a natural NO carrier, with the glutathione transferase superfamily: suggestion for an evolutionary pressure in the direction of the storage of nitric oxide
- Author
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DE MARIA F, PEDERSEN JZ, CACCURI AM, TURELLA P, STELLA L, LO BELLO M, FEDERICI G, RICCI G., ANTONINI, GIOVANNI, DE MARIA, F, Pedersen, Jz, Caccuri, Am, Antonini, Giovanni, Turella, P, Stella, L, LO BELLO, M, Federici, G, and Ricci, G.
- Subjects
Settore BIO/10 - Published
- 2003
15. The thin line between cell-penetrating and antimicrobial peptides: the case of Pep-1 and Pep-1-K
- Author
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Bobone, S, Piazzon, A, Orioni, B, Pedersen, Jz, Nan, Y, Hahm, K, Shin, S, and Stella, L
- Subjects
liposomes ,water–membrane partition ,fluorescence spectroscopy ,ion leakage ,Settore BIO/10 ,Settore CHIM/02 - Chimica Fisica - Published
- 2011
16. Theoretical and experimental studies on the structure-antioxidant activity relationship of the synthetic 4-methylcoumarins
- Author
-
Barzegar, A, Davari, M, Chaparzadeh, N, Zarghami, N, Pedersen, Jz, Incerpi, S, Saso, L, and Moosavi Movahedi, A
- Subjects
Coumarins ,Free radical ,Coumarins, Reactive oxygen species, Antioxidant, Reducing power, Free radical, B3LYP method ,B3LYP method ,Antioxidant ,Settore BIO/10 ,Reactive oxygen species ,Reducing power - Published
- 2011
17. Hydrogel nanoparticles for enzyme-based therapies
- Author
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Bobone, S, Miele, E, Cerroni, B, Nicolai, E, DI VENERE, A, Polini, R, Pedersen, Jz, Paradossi, G, Rosato, N, and Stella, L
- Subjects
Settore CHIM/02 - Chimica Fisica - Published
- 2010
18. Antioxidant activity of 4-methylcoumarin compounds
- Author
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Pedersen, Jz, Oliveira, C, Incerpi, S, Kumar, V, Fiore, A, DE VITO, P, Prasad, A, Malhotra, S, Parmar, V, and Saso, L
- Subjects
Coumarins ,antioxidants ,electron spin resonance ,radicals ,intracellular ,fluorescence ,Settore BIO/10 - Published
- 2007
19. Glutathione transferases sequester toxic dinitrosyl-iron complexes in cells: a protection mechanism against excess nitric oxide
- Author
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Pedersen, Jz, DE MARIA, F, Turella, P, Federici, G, Mattei, M, Fabrini, R, Dawood, Kf, Massimi, Mara, Caccuri, Am, and Ricci, G.
- Subjects
Male ,Rats, Sprague-Dawley ,Glutathione S-Transferase pi ,Iron ,Hepatocytes ,Animals ,Humans ,Nitrogen Oxides ,Settore BIO/10 ,Nitric Oxide ,Cells, Cultured ,Glutathione Transferase ,Rats - Abstract
It is now well established that exposure of cells and tissues to nitric oxide leads to the formation of a dinitrosyl-iron complex bound to intracellular proteins, but little is known about how the complex is formed, the identity of the proteins, and the physiological role of this process. By using EPR spectroscopy and enzyme activity measurements to study the mechanism in hepatocytes, we here identify the complex as a dinitrosyl-diglutathionyl-iron complex (DNDGIC) bound to Alpha class glutathione S-transferases (GSTs) with extraordinary high affinity (K(D) = 10(-10) m). This complex is formed spontaneously through NO-mediated extraction of iron from ferritin and transferrin, in a reaction that requires only glutathione. In hepatocytes, DNDGIC may reach concentrations of 0.19 mm, apparently entirely bound to Alpha class GSTs, present in the cytosol at a concentration of about 0.3 mm. Surprisingly, about 20% of the dinitrosyl-glutathionyl-iron complex-GST is found to be associated with subcellular components, mainly the nucleus, as demonstrated in the accompanying paper (Stella, L., Pallottini, V., Moreno, S., Leoni, S., De Maria, F., Turella, P., Federici, G., Fabrini, R., Dawood, K. F., Lo Bello, M., Pedersen, J. Z., and Ricci, G. (2007) J. Biol. Chem. 282, 6372-6379). DNDGIC is a potent irreversible inhibitor of glutathione reductase, but the strong complex-GST interaction ensures full protection of glutathione reductase activity in the cells, and in vitro experiments show that damage to the reductase only occurs when the DNDGIC concentration exceeds the binding capacity of the intracellular GST pool. Because Pi class GSTs may exert a similar role in other cell types, we suggest that specific sequestering of DNDGIC by GSTs is a physiological protective mechanism operating in conditions of excessive levels of nitric oxide.
- Published
- 2007
20. Membrane topology and mechanism of pore formation of the antibiotic lipopeptide trichogin GA IV
- Author
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Mazzuca, C, Stella, L, Venanzi, M, Pedersen, Jz, Moroder, L, Didonè, M, Formaggio, F, Toniolo, C, and Pispisa, B
- Subjects
Settore CHIM/02 - Chimica Fisica - Published
- 2005
21. Human glutathione transferase P1-1 and nitric oxide carriers; a new role for an old enzyme
- Author
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LO BELLO, M, Nuccetelli, M, Caccuri, Am, Stella, L, Parker, M, Rossjohn, J, Mckinstry, W, Mozzi, A, Federici, G, Polizio, F, Pedersen, Jz, and Ricci, G
- Subjects
Mass Spectrometry ,Glutathione ,Humans ,Glutathione Transferase ,Protein Binding ,Nitric Oxide ,Glutathione S-Transferase pi ,Nitrogen Oxides ,Electron Spin Resonance Spectroscopy ,Binding, Competitive ,S-Nitrosoglutathione ,Isoenzymes ,Iron ,Serum Albumin ,Binding ,Competitive ,Settore BIO/10 - Abstract
S-Nitrosoglutathione and the dinitrosyl-diglutathionyl iron complex are involved in the storage and transport of NO in biological systems. Their interactions with the human glutathione transferase P1-1 may reveal an additional physiological role for this enzyme. In the absence of GSH, S-nitrosoglutathione causes rapid and stable S-nitrosylation of both the Cys(47) and Cys(101) residues. Ion spray ionization-mass spectrometry ruled out the possibility of S-glutathionylation and confirms the occurrence of a poly-S-nitrosylation in GST P1-1. S-Nitrosylation of Cys(47) lowers the affinity 10-fold for GSH, but this negative effect is minimized by a half-site reactivity mechanism that protects one Cys(47)/dimer from nitrosylation. Thus, glutathione transferase P1-1, retaining most of its original activity, may act as a NO carrier protein when GSH depletion occurs in the cell. The dinitrosyl-diglutathionyl iron complex, which is formed by S-nitrosoglutathione decomposition in the presence of physiological concentrations of GSH and traces of ferrous ions, binds with extraordinary affinity to one active site of this dimeric enzyme (K(i)10(-12) m) and triggers negative cooperativity in the vacant subunit (K(i) = 10(-9) m). The complex bound to the enzyme is stable for hours, whereas in the free form and at low concentrations, its life time is only a few minutes. ESR and molecular modeling studies provide a reasonable explanation of this strong interaction, suggesting that Tyr(7) and enzyme-bound GSH could be involved in the coordination of the iron atom. All of the observed findings suggest that glutathione transferase P1-1, by means of an intersubunit communication, may act as a NO carrier under different cellular conditions while maintaining its well known detoxificating activity toward dangerous compounds.
- Published
- 2001
22. Deprotonation of low-spin mononuclear iron(III)-hydroperoxide complexes give transient blue species assigned to high-spin iron(III)-peroxide complexes
- Author
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Jensen, Kb, Mckenzie, Cj, Nielsen, Lp, Pedersen, Jz, and Svendsen, Hm
- Subjects
Settore BIO/10 - Published
- 1999
23. Formation and stability of vicine radicals studied by electron spin resonance
- Author
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Musci, G, Pedersen, Jz, and Rotilio, G
- Subjects
Settore BIO/10 - Published
- 1989
24. Metronidazole-resistant clinical isolates of Trichomonas vaginalis maintain low intracellular metronidazole radical anion levels as a consequence of defective oxygen scavenging
- Author
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Lloyd, D, Yarlett, N, Yarlett, Nc, Pedersen, Jz, and Kristensen, B
- Subjects
Settore BIO/10 - Published
- 1986
25. Tetrac and NDAT Induce Anti-proliferation via Integrin αvβ3 in Colorectal Cancers With Different
- Author
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Yu-Tang Chin, Zong-Rong He, Chi-Long Chen, Hsiao-Ching Chu, Yih Ho, Po-Yu Su, Yu-Chen S. H. Yang, Kuan Wang, Ya-Jung Shih, Yi-Ru Chen, Jens Z. Pedersen, Sandra Incerpi, André Wendindondé Nana, Heng-Yuan Tang, Hung-Yun Lin, Shaker A. Mousa, Paul J. Davis, Jacqueline Whang-Peng, Chin, Yt, He, Zr, Chen, Cl, Chu, Hc, Ho, Y, Su, Py, Yang, Ysh, Wang, K, Shih, Yj, Chen, Yr, Pedersen, Jz, Incerpi, S, Nana, Aw, Tang, Hy, Lin, Hy, Mousa, Sa, Davis, Pj, and Whang-Peng, J.
- Subjects
0301 basic medicine ,Drug ,Colorectal cancer ,NDAT ,Endocrinology, Diabetes and Metabolism ,media_common.quotation_subject ,Integrin ,030209 endocrinology & metabolism ,Drug resistance ,anticancer ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,phosphoERK1/2 ,03 medical and health sciences ,Endocrinology ,0302 clinical medicine ,tetrac ,medicine ,Settore BIO/10 ,media_common ,colorectal cancer cells ,lcsh:RC648-665 ,integrin αvβ3 ,perfusion bellows cell culture system ,biology ,business.industry ,Wild type ,Correction ,medicine.disease ,In vitro ,030104 developmental biology ,Cell culture ,Cancer research ,biology.protein ,Hormone analog ,business ,perfusion bellows cell culture system, colorectal cancer cells, anticancer, phosphoERK1/2, NDAT, tetrac, integrin αvβ3 - Abstract
Colorectal cancer is a serious medical problem in Taiwan. New, effective therapeutic approaches are needed. The selection of promising anticancer drugs and the transition from pre-clinical investigations to clinical trials are often challenging. The deaminated thyroid hormone analog (tetraiodothyroacetic acid, tetrac) and its nanoparticulate analog (NDAT) have been shown to have anti-proliferative activity in vitro and in xenograft model of different neoplasms, including colorectal cancers. However, mechanisms involved in tetrac- and NDAT-induced anti-proliferation in colorectal cancers are incompletely understood. We have investigated possible mechanisms of tetrac and NDAT action in colorectal cancer cells, using a perfusion bellows cell culture system that allows efficient, large-scale screening for mechanisms of drug actions on tumor cells. Although integrin αvβ3 in K-RAS wild type colorectal cancer HT-29 cells was far less than that in K-RAS mutant HCT116 cells, HT-29 was more sensitive to both tetrac and NDAT. Results also indicate that both tetrac and NDAT bind to tumor cell surface integrin αvβ3, and the agents may have different mechanisms of anti-proliferation in colorectal cancer cells. K-RAS status appears to play an important role in drug resistance that may be encountered in treatment with this drug combination.
- Published
- 2019
26. Probing antioxidant activity of 2′-hydroxychalcones: Crystal and molecular structures, in vitro antiproliferative studies and in vivo effects on glucose regulation
- Author
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Jaroslav Miler, Genevieve Lidoff, Miriam Rossi, Celia A. McKee, Jens Z. Pedersen, Sharon Lee, Charles Caldwell, Valentina Balducci, Erica J. Crespi, Gail Nakano, Francis Baffour, Sandra Incerpi, Manasi Jiwrajka, Michelle Duong, Dylan Alex Karlin, Stefano Leone, Francesco Caruso, Rossi, M, Caruso, F, Crespi J., E, Pedersen, Jz, Nakano, G, Duong, M, Mckee, C, Lee, S, Jiwrajka, M, Caldwell, C, Baffour, F, Karlin, D, Lidoff, G, Leone, S, Balducci, V, Miler, J, and Incerpi, Sandra
- Subjects
Blood Glucose ,Male ,Antioxidant ,DPPH ,medicine.medical_treatment ,THP-1 monocyte ,Crystal structure ,Crystallography, X-Ray ,Biochemistry ,Antioxidants ,Monocytes ,Myoblasts ,2,2′,5′-trihydroxychalcone ,chemistry.chemical_compound ,Chalcones ,Picrates ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,Insulin ,Obesity ,Settore BIO/10 ,Cell Proliferation ,L-6 myoblasts ,Biphenyl Compounds ,Body Weight ,General Medicine ,Fibroblasts ,Free radical scavenger ,In vitro ,Rats ,Rats, Zucker ,chemistry ,Polyphenol ,Biophysics ,Female ,Anti-Obesity Agents ,Single crystal - Abstract
In order to better understand the antioxidant behavior of a series of polyphenolic 2'-hydroxychalcones, we describe the results of several chemical and biological studies, in vitro and in vivo. Single crystal X-ray methods elucidated their molecular structures and important intermolecular interactions such as H-bonding and molecular stacking in the crystal structures that contribute to our knowledge in explaining antioxidant activity. The results of experiments using the 1,1-diphenyl-2-dipicrylhydrazyl (DPPH) UV-vis spectroscopic method indicate that a hydroxyl group in position 5' induces the highest antioxidant activity. Consequently, 2,2',5'-trihydroxychalcone was selected for further study in vitro towards ROS scavenging in L-6 myoblasts and THP-1 human monocytes, where it shows an excellent antioxidant activity in a concentration range lower than that reported by most studies of related molecules. In addition, this chalcone shows a very selective activity: it inhibits the proliferation of leukemic cells, but it does not affect the normal L-6 myoblasts and human fibroblasts. In studying 2,2',5'-trihydroxychalcone's effect on weight gain and serum glucose and insulin levels in Zucker fatty (fa(-)/fa(-)) rats we found that supplementing the diet with a 10 mg/kg dose of this chalcone (3 times weekly) blunted the increase in glucose that co-occurs with weight gain over the 6-week treatment period. It is concluded that 2,2',5'-trihydroxychalcone has the potential to serve as a protective agent for some debilitating diseases.
- Published
- 2013
27. The mechanism of antioxidant activity of IRFI005 as a synthetic hydrophilic analogue of vitamin E
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Luciano Saso, Ali Akbar Moosavi-Movahedi, Sandra Incerpi, Jens Z. Pedersen, Abolfazl Barzegar, Barzegar, A, Pedersen, Jz, Incerpi, Sandra, MOOSAVI MOVAHEDI, Aa, and Saso, L.
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Vitamin ,IRFI005 ,Antioxidant ,Cell Survival ,Raxofelast ,medicine.medical_treatment ,Radical ,medicine.disease_cause ,Biochemistry ,Antioxidants ,chemistry.chemical_compound ,Semi-empirical calculations ,Free radical ,ROS ,Hyperchem ,ESR ,Reducing power ,medicine ,Animals ,Vitamin E ,Molecule ,Settore BIO/10 ,Cells, Cultured ,Benzofurans ,Chemistry ,Electron Spin Resonance Spectroscopy ,General Medicine ,Rats ,Membrane ,antioxidant ,esr ,free radical ,hyperchem ,irfi005 ,raxofelast ,reducing power ,ros ,semi-empirical calculations ,Reactive Oxygen Species ,Intracellular ,Oxidative stress - Abstract
Developing a rational strategy to control intracellular reactive oxygen species (ROS) requires understanding the mechanism of antioxidant activity. In this investigation the properties of a novel synthetic analog of vitamin E (IRFI005) with potent antioxidant activity are described. A mechanism is proposed for its efficient radical-scavenging effects. Cellular antioxidant and antitoxicity assays showed IRFI005 to freely permeate across cellular membranes, enabling it to be an effective suppressor of intracellular ROS and to protect cells against toxicity induced by free radical generating compounds. The free radical-scavenging activity of IRFI005 examined by UV-Vis and electron spin resonance (ESR) techniques clearly confirmed a "two electrons and/or H-atom" donation mechanism for each molecule of IRFI005. Reducing power assay as well as semi-empirical calculations revealed that under physiological conditions (pH∼7) almost all IRFI005 molecules are in the anionic state (IRFI005(-)). Data indicated that the electron donating ability of IRFI005(-) was dominant at physiological pH because of higher stability of quinine-IRFI005(-) and less barrier energy of IRFI005(-) than neutral IRFI005. Consequently, the efficient cellular protection of IRFI005 against toxic free radicals can be explained by a two electron-transfer process, because of reduced inter-frontier molecular orbital energy gap barrier at physiological pH. Our findings suggest that hydrophilic vitamin E-like antioxidants are good candidates in designing novel therapeutic strategies for inhibition of oxidative stress associated with different human diseases.
- Published
- 2011
28. Nongenomic actions of thyroid hormones: from basic research to clinical applications. An update
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Faith B. Davis, Ricardo N. Farías, Paolo De Vito, R.G. Ahmed, Paolo Luly, Jens Z. Pedersen, Sandra Incerpi, Paul J. Davis, Ahmed, Rg, Davis P., J, Davis, Fb, De Vito, P, Farias R., N, Luly, P, Pedersen, Jz, and Incerpi, Sandra
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Pharmacology ,MAPK/ERK pathway ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Thyroid ,Peptide hormone ,Biology ,cardiovascular system, immune system, integrin, ion transport, MAPK, mTOR Na/K-ATPase, nerve cells ,Settore BIO/09 ,Cell biology ,medicine.anatomical_structure ,Endocrinology ,Cell surface receptor ,Internal medicine ,medicine ,STAT protein ,Immunology and Allergy ,Receptor ,PI3K/AKT/mTOR pathway ,Hormone - Abstract
Extranuclear or nongenomic actions of thyroid hormones are unaffected by the inhibitors of protein synthesis, their site of action has been localized at the plasma membrane but also in the cytoplasm and organelles such as the mitochondria. This review takes into account recent major advances in nongenomic effects of thyroid hormones in nervous system, immune system and cardiovascular tissue, with a particular focus on the plasma membrane receptor integrin αvβ3. In nerve cells nongenomic effects of thyroid hormones point mainly to a direct modulation of several channels/receptors for the major neurotransmitters, even though more complex pathways have also been demonstrated. Certain neuroprotective actions have recently been described for thyronamines, and this may be relevant to Alzheimer's disease and multiple sclerosis. The immune system is also modulated nongenomically by thyroid hormones, through potentiation of the effects of cytokines such as IFN-γ or lipopolysaccharide, or through activators of STAT protein leading to activation of the mammalian target of rapamycin (mTOR) pathway, a highly conserved kinase downstream target of nongenomic actions of thyroid hormone. The mTOR system is also involved in the cardioprotection mechanisms, where thyroid hormone signaling through the receptor integrin αvβ3 may play an important role that needs to be further studied. The identification of integrin αvβ3 as a plasma membrane receptor for thyroid hormones has provided a new perspective on the role of these hormones in cellular defense. Analogs of thyroid hormones, inhibitors and agonists at the integrin receptor for the hormone and mTOR inhibitors are evaluated as areas of emphasis for therapeutic research.
- Published
- 2013
29. Protection of Cells against Oxidative Stress by Nanomolar Levels of Hydroxyflavones Indicates a New Type of Intracellular Antioxidant Mechanism
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Tomáš Filipský, Paolo Bovicelli, Sandra Incerpi, Veronika Staňková, Paolo Luly, Jan Hajek, Ilaria Proietti Silvestri, Paolo De Vito, Emanuele Lombardo, Valentina Balducci, Eugenia I. Bavavea, Giuliana Righi, Jens Z. Pedersen, Cristian Sabellico, Stefano Leone, Luciano Saso, Lombardo, E, Sabellico, C, Hájek, J, Staňková, V, Filipský, T, Balducci, Valentina, De Vito, P, Leone, Stefano, Bavavea, Ei, Silvestri, Ip, Righi, G, Luly, P, Saso, L, Bovicelli, P, Pedersen, Jz, and Incerpi, Sandra
- Subjects
Anatomy and Physiology ,Antioxidant ,medicine.medical_treatment ,lcsh:Medicine ,BAICALEIN ,medicine.disease_cause ,Biochemistry ,ACTIVATION ,Oxidative Damage ,chemistry.chemical_compound ,0302 clinical medicine ,Basic Cancer Research ,oxidative stress ,humans ,lcsh:Science ,VITAMIN-E ,chemistry.chemical_classification ,0303 health sciences ,Multidisciplinary ,2'-HYDROXYCHALCONES ,myoblasts ,WOGONIN ,Chemical Reactions ,PROLIFERATION ,drug ,flavanones ,cell line ,free radical scavengers ,APOPTOSIS ,animals ,Chemistry ,antioxidants ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Quercetin ,monocytes ,Intracellular ,Research Article ,Cell Physiology ,INHIBITION ,Organic Radicals ,dose-response relationship ,flavones ,drug effects ,pharmacology ,cell survival ,rats ,Flavones ,03 medical and health sciences ,Chemical Biology ,medicine ,Settore BIO/10 ,Biology ,030304 developmental biology ,Dose-Response Relationship, Drug ,Organic Chemistry ,lcsh:R ,FLAVONOIDS ,SCUTELLARIA ,Baicalein ,chemistry ,Small Molecules ,Polyphenol ,Cumene hydroperoxide ,lcsh:Q ,Oxidative stress - Abstract
Natural polyphenol compounds are often good antioxidants, but they also cause damage to cells through more or less specific interactions with proteins. To distinguish antioxidant activity from cytotoxic effects we have tested four structurally related hydroxyflavones (baicalein, mosloflavone, negletein, and 5,6-dihydroxyflavone) at very low and physiologically relevant levels, using two different cell lines, L-6 myoblasts and THP-1 monocytes. Measurements using intracellular fluorescent probes and electron paramagnetic resonance spectroscopy in combination with cytotoxicity assays showed strong antioxidant activities for baicalein and 5,6-dihydroxyflavone at picomolar concentrations, while 10 nM partially protected monocytes against the strong oxidative stress induced by 200 mu M cumene hydroperoxide. Wide range dose-dependence curves were introduced to characterize and distinguish the mechanism and targets of different flavone antioxidants, and identify cytotoxic effects which only became detectable at micromolar concentrations. Analysis of these dose-dependence curves made it possible to exclude a protein-mediated antioxidant response, as well as a mechanism based on the simple stoichiometric scavenging of radicals. The results demonstrate that these flavones do not act on the same radicals as the flavonol quercetin. Considering the normal concentrations of all the endogenous antioxidants in cells, the addition of picomolar or nanomolar levels of these flavones should not be expected to produce any detectable increase in the total cellular antioxidant capacity. The significant intracellular antioxidant activity observed with 1 pM baicalein means that it must be scavenging radicals that for some reason are not eliminated by the endogenous antioxidants. The strong antioxidant effects found suggest these flavones, as well as quercetin and similar polyphenolic antioxidants, at physiologically relevant concentrations act as redox mediators to enable endogenous antioxidants to reach and scavenge different pools of otherwise inaccessible radicals.
- Published
- 2013
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30. Nongenomic effects of thyroid hormones on the immune system cells: New targets, old players
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Paolo De Vito, Zulema A. Percario, Stefano Leone, Sandra Incerpi, Elisabetta Affabris, Giorgio Mangino, Valentina Balducci, Paul J. Davis, Paolo Luly, Faith B. Davis, Jens Z. Pedersen, DE VITO, P, Balducci, V, Leone, S, Percario, Z, Mangino, G, Davis, Pj, Davis, Fb, Affabris, Elisabetta, Luly, P, Pedersen, Jz, and Incerpi, Sandra
- Subjects
medicine.medical_specialty ,Integrins ,Thyroid Hormones ,cell migration ,rgd ,Clinical Biochemistry ,Receptors, Cytoplasmic and Nuclear ,Biology ,integrin alpha v beta 3 ,Settore BIO/09 ,Biochemistry ,Tetrac ,Endocrinology ,Immune system ,Cell surface receptor ,tetrac ,Internal medicine ,medicine ,Animals ,Humans ,Integrin avb3 ,Receptor ,Molecular Biology ,PI3K/AKT/mTOR pathway ,reactive oxygen species ,Pharmacology ,RGD ,Genome, Human ,TOR Serine-Threonine Kinases ,Organic Chemistry ,Thyroid ,integrin αvβ3 ,Cell migration ,Cell biology ,medicine.anatomical_structure ,Nuclear receptor ,nongenomic effect ,Immune System ,Reactive Oxygen Species ,Hormone - Abstract
""It is now widely accepted that thyroid hormones, L-thyroxine (T4) and 3,30,5-triiodo-L-thyronine (T3), act. as modulators of the immune response. Immune functions such as chemotaxis, phagocytosis, generation. of reactive oxygen species, and cytokine synthesis and release, are altered in hypo- and hyper-thyroid. conditions, even though for many immune cells no clear correlation has been found between altered levels. of T3 or T4 and effects on the immune responses. Integrins are extracellular matrix proteins that are. important modulators of many cellular responses, and the integrin avb3 has been identified as a cell surface. receptor for thyroid hormones. Rapid signaling via this plasma membrane binding site appears to be. responsible for many nongenomic effects of thyroid hormones, independent of the classic nuclear receptors.. Through the integrin avb3 receptor the hormone can activate both the ERK1\\\/2 and phosphatidylinositol. 3-kinase pathways, with downstream effects including intracellular protein trafficking,. angiogenesis and tumor cell proliferation. It has recently become clear that an important downstream. target of the thyroid hormone nongenomic pathway may be the mammalian target of rapamycin, mTOR.. New results demonstrate the capability of T3 or T4 to induce in the short time range important responses. related to the immune function, such as reactive oxygen species production and cell migration in THP-1. monocytes. Thus thyroid hormones seem to be able to modulate the immune system by a combination of. rapid nongenomic responses interacting with the classical nuclear response.. ""
- Published
- 2011
31. Short-term effects of thyroid hormones during development: Focus on signal transduction
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Sandra Incerpi, Jens Z. Pedersen, Silvana Spagnuolo, Sergio Scapin, Paolo Luly, Silvia Leoni, Paolo De Vito, Davide Gnocchi, Scapin, S, Leoni, S, Spagnuolo, S, Gnocchi, D, DE VITO, P, Luly, P, Pedersen, Jz, and Incerpi, Sandra
- Subjects
Na+/K+ ATPase ,medicine.medical_specialty ,Na/K-ATPase ,Thyroid Hormones ,Clinical Biochemistry ,Peptide hormone ,Biology ,Biochemistry ,Settore BIO/09 ,Integrin alphaVbeta3 ,Sodium-Potassium-Exchanging ATPase ,Signal Transduction ,Animals ,Humans ,Thyroid hormone receptor beta ,non genomic ,Endocrinology ,Cell surface receptor ,Internal medicine ,hepatocyte ,medicine ,chick embryo ,Settore BIO/10 ,Molecular Biology ,development ,Pharmacology ,Thyroid hormone receptor ,Organic Chemistry ,Thyroid ,thyroid hormone ,medicine.anatomical_structure ,Nuclear receptor ,Signal transduction ,Hormone - Abstract
Extranuclear or nongenomic effects of thyroid hormones are mediated by receptors located at the plasma membrane or inside cells, and are independent of protein synthesis. Recently the alphaVbeta3 integrin was identified as a cell membrane receptor for thyroid hormones, and a wide variety of nongenomic effects have now been shown to be induced through binding of thyroid hormones to this receptor. However, also other thyroid hormone receptors can produce nongenomic effects, including the cytoplasmic TRalpha and TRbeta receptors and probably also a G protein-coupled membrane receptor, and increasing importance is now given to thyroid hormone metabolites like 3,5-diiodothyronine and reverse T(3) that can mimick some nongenomic effects of T(3) and T(4). Signal transduction from the alphaVbeta3 integrin may proceed through at least three independent pathways (protein kinase C, Src or mitogen-activated kinases) but the details are still unknown. Thyroid hormones induce nongenomic effects on at least three important Na(+)-dependent transport systems, the Na(+)/K(+)-ATPase, the Na(+)/H(+) exchanger, and amino acid transport System A, leading to a mitogenic response in embryo cells; but modulation of the same transport systems may have different roles in other cells and at different developmental stages. It seems that thyroid hormones in many cases can modulate nongenomically the same targets affected by the nuclear receptors through long-term mechanisms. Recent results on nongenomic effects confirm the old theory that the primary role of thyroid hormones is to keep the steady-state level of functioning of the cell, but more and more mechanisms are discovered by which this goal can be achieved.
- Published
- 2010
32. Atrial natriuretic peptide and oxidative stress
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Jens Z. Pedersen, Sandra Incerpi, Paolo De Vito, Paolo Luly, DE VITO, P, Incerpi, Sandra, Pedersen, Jz, and Luly, P.
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medicine.medical_specialty ,Physiology ,NADPH Oxidase ,Biology ,medicine.disease_cause ,Settore BIO/09 ,Biochemistry ,Natriuresis ,Cellular and Molecular Neuroscience ,Paracrine signalling ,Endocrinology ,Atrial natriuretic peptide ,Internal medicine ,Receptors ,medicine ,Animals ,Humans ,Autocrine signalling ,Cyclic GMP ,Diacylglycerol kinase ,NADPH Oxidases ,Oxidative Stress ,Reactive Oxygen Species ,Receptors, Atrial Natriuretic Factor ,Atrial Natriuretic Factor ,cardiovascular system ,Signal transduction ,hormones, hormone substitutes, and hormone antagonists ,Oxidative stress ,Homeostasis - Abstract
Atrial natriuretic peptide (ANP) is a hormone, produced mainly by cardiomyocytes, with a major role in cardiovascular homeostatic mechanisms such as natriuresis and vasodilation, which serve to regulate blood pressure. However, ANP also acts as an autocrine/paracrine factor on other targets such as kidney, lung, thymus, liver and the immune system. ANP participates in the regulation of cell growth and proliferation, and evidence is accumulating that these effects are associated with the generation of reactive oxygen species (ROS). In vascular cells and cardiomyocytes ANP stimulates the antioxidant defense, but in other systems such as hepatoblastoma and macrophages ANP may produce either antioxidant or prooxidant effects, depending on experimental conditions and cell context. At present very little is known on the relationship between ANP and ROS production in the normal homeostatic processes or during the development of cardiovascular diseases and cancer. Our current knowledge of the role of ANP in signaling pathways leading to the generation of intracellular messengers such as diacylglycerol (DAG), and guanosine 3'-5'-cyclic monophosphate has been examined in order to clarify the mechanisms by which the hormone may counteract or contribute to the potentially dangerous effects of free radicals.
- Published
- 2009
33. Involvement of plasma membrane redox systems in hormone action
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Paolo De Vito, Jens Z. Pedersen, Sandra Incerpi, Anna Maria Fiore, Incerpi, Sandra, Fiore, Am, DE VITO, P, and Pedersen, Jz
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Antioxidant ,medicine.medical_treatment ,Pharmaceutical Science ,Biology ,Models, Biological ,Steroid ,medicine ,Animals ,Humans ,Insulin ,Settore BIO/10 ,Pharmacology ,chemistry.chemical_classification ,Cartoons as Topic ,Reactive oxygen species ,Vitamin E ,Cell Membrane ,Metabolism ,Hormones ,Cell biology ,Enzyme ,chemistry ,Biochemistry ,Signal transduction ,Reactive Oxygen Species ,Oxidation-Reduction ,Signal Transduction ,Hormone - Abstract
Reactive oxygen species (ROS) is the common name used to describe the partially reduced forms of molecular oxygen that may be generated in cells during oxidative metabolism. They are normally considered to be toxic, and cells possess various defence systems to protect themselves including antioxidant enzymes and low molecular weight antioxidants like vitamin C and vitamin E. However, it is now clear that small amounts of ROS also act as messenger molecules in cell signal transduction pathways; the plasma membrane of eukaryotic cells in particular contains a variety of different ROS-producing oxidases and reductases, of which the best characterized are the superoxide-producing NADPH oxidases. It has been known for many years that membrane redox activity can be changed rapidly by various hormones and growth factors, but the molecular mechanisms involved and the physiological importance of this phenomenon have only recently begun to be unveiled. This review summarizes the state of the art on plasma membrane-based ROS signalling in the pathways of insulin, steroid and thyroid hormones and growth factors. The apparent paradox of ROS being essential biomolecules in the regulation of cellular functions, but also toxic by-products of metabolism, may be important for the pharmacological application of natural and synthetic antioxidants.
- Published
- 2007
34. Nongenomic actions of thyroid hormones: focus on membrane transport systems
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Rn Farias, Jz Pedersen, Sandra Incerpi, Am Fiore, Farias, Rn, Fiore, Am, Pedersen, Jz, and Incerpi, Sandra
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Pharmacology ,amino acid transport ,Na+/K+-ATPase ,Endocrinology, Diabetes and Metabolism ,Endoplasmic reticulum ,Thyroid ,Thyroid hormone, ion transport, Ca2+-transport, Na+/H+ exchanger, Na+/K+-ATPase, amino acid transport ,Membrane transport ,Biology ,Cell biology ,Thyroid hormone ,ion transport ,Cytosol ,medicine.anatomical_structure ,Na+/H+ exchanger ,Nuclear receptor ,Biochemistry ,Extracellular ,medicine ,Ca2+-transport ,Immunology and Allergy ,Settore BIO/10 ,Receptor ,Hormone - Abstract
Extranuclear or nongenomic effects of thyroid hormones are unaffected by inhibitors of protein synthesis, and their rapid time course cannot be explained by interaction of the hormone molecule with nuclear receptors. Their origin has been localized at the plasma membrane, but also at organelles such as the endoplasmatic reticulum and mitochondria. Thyroid hormone has been reported to activate, by both genomic and non genomic mechanisms, the Ca2+-ATPase that stores calcium from the cytosol in the sarcoplasmic reticulum; the decrease in intracellular Ca2+ leads to muscle relaxation. Considering the important effects on the cardiovascular system, T3 can actually be envisaged as a potent inotropic drug. T3 is also a major regulator of the plasma membrane Na+/K+-ATPase activity; T3 and its analog 3,5-diiodothyronine rapidly inhibits Na+/K+-ATPase in chick embryo hepatocytes, whereas the activity is up-regulated in alveolar epithelial cells. Also the ubiquitous plasma membrane Na+/H+ exchanger, that regulates cell volume and pH by exchanging extracellular Na+ with cytoplasmic H+ according to the concentration gradient, is activated by T3 via both genomic and nongenomic mechanisms. A growing number of natural and synthetic thyroid hormone analogs are available to study the physiological importance of extranuclear effects; this may lead to compounds that selectively target either genomic or nongenomic receptors. Such drugs may make it possible to activate separately only a part of the complex effects normally induced by thyroid hormones, this could be of clinical relevance for the cardiovascular system, bone tissue and the Central Nervous System.
- Published
- 2006
35. Role of thyroid hormones in insulin resistance and diabetes
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Elena Candelotti, Jens Z. Pedersen, Paolo Luly, R G Ahmed, Paul J. Davis, Paolo De Vito, Sandra Incerpi, De Vito, P, Candelotti, Elena, Ahmed, R. G., Luly, P, Davis, Pj, Incerpi, Sandra, and Pedersen, Jz
- Subjects
Pharmacology ,medicine.medical_specialty ,endocrine system diseases ,business.industry ,Endocrinology, Diabetes and Metabolism ,Inflammation ,medicine.disease ,medicine.disease_cause ,Settore BIO/09 ,Diabetes, hormone crosstalk, hyperthyroidism, hypothyroidism, inflammation, insulin resistance, oxidative stress, thyroid hormones ,Insulin resistance ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Thyroid hormones ,medicine ,Immunology and Allergy ,Settore BIO/10 ,medicine.symptom ,business ,Oxidative stress - Abstract
Several recent studies suggest that thyroid hormones role is not completely understood in insulin resistance as well as in the development of type 2 diabetes mellitus. Through the perturbation of gene expression linked to glucose metabolism both hyper- and hypothyroidism may cause impaired glucose utilization in skeletal muscle or overproduction of hepatic glucose, thus contributing to the induction of insulin resistance. The complex crosstalk between immune cells and skeletal muscle cells and adipose tissue, the ability of macrophages to release thyroid hormones, the ability of T3 to induce M2 macrophage polarization, the proinflammatory role of thyroid hormones and the antinflammatory effects of insulin all represent important events where thyroid hormone interference may lead to insulin resistance. The crosstalk between thyroid hormones and insulin in the modulation of oxidative status, and also to some extent in the antagonistic effects on several aspects of mitochondrial activities, could represent novel downstream targets for future therapeutic strategies in the treatment of insulin resistance and type 2 diabetes.
36. Progesterone modulates cell growth via integrin αvβ3-dependent pathway in progesterone receptor-negative MDA-MB-231 cells.
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Tsai CC, Yang YN, Wang K, Chen YE, Chen YF, Yang JC, Li ZL, Huang HM, Pedersen JZ, Incerpi S, Lee SY, Lin HY, and Whang-Peng J
- Abstract
Progesterone (P
4 ) plays a pivotal role in regulating the cancer progression of various types, including breast cancer, primarily through its interaction with the P4 receptor (PR). In PR-negative breast cancer cells, P4 appears to function in mediating cancer progression, such as cell growth. However, the mechanisms underlying the roles of P4 in PR-negative breast cancer cells remain incompletely understood. This study aimed to investigate the effects of P4 on cell proliferation, gene expression, and signal transduction in PR-negative MDA-MB-231 breast cancer cells. P4 -activated genes, associated with proliferation in breast cancer cells, exhibit a stimulating effect on cell growth in PR-negative MDA-MB-231 cells, while demonstrating an inhibitory impact in PR-positive MCF-7 cells. The use of arginine-glycine-aspartate (RGD) peptide successfully blocked P4 -induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, aligning with computational models of P4 binding to integrin αvβ3. Disrupting integrin αvβ3 binding with RGD peptide or anti-integrin αvβ3 antibody altered P4 -induced expression of proliferative genes and modified P4 -induced cell growth in breast cancer cells. In conclusion, integrin αvβ3 appears to mediate P4 -induced ERK1/2 signal pathway to regulate proliferation via alteration of proliferation-related gene expression in PR-negative breast cancer cells., Competing Interests: 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., (© 2024 The Authors. Published by Elsevier Ltd.)- Published
- 2024
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37. Editorial: Crosstalk between thyroid hormones, analogs and ligands of integrin αvβ3 in health and disease. Who is talking now?
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Incerpi S, Ashur-Fabian O, Davis PJ, and Pedersen JZ
- Subjects
- Ligands, Receptors, Thyroid Hormone, Cell Physiological Phenomena, Integrin alphaVbeta3, Thyroid Hormones
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
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38. Extranuclear effects of thyroid hormones and analogs during development: An old mechanism with emerging roles.
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Incerpi S, Gionfra F, De Luca R, Candelotti E, De Vito P, Percario ZA, Leone S, Gnocchi D, Rossi M, Caruso F, Scapin S, Davis PJ, Lin HY, Affabris E, and Pedersen JZ
- Subjects
- Adenosine Triphosphatases metabolism, Amino Acid Transport System A, Cyclic AMP-Dependent Protein Kinases metabolism, Glucose, Humans, Integrins metabolism, Mitogens, Protein Kinase C metabolism, Thyroid Hormones metabolism, Thyroxine metabolism, Neoplasms metabolism, Triiodothyronine physiology
- Abstract
Thyroid hormones, T
3 (triiodothyronine) and T4 (thyroxine), induce a variety of long-term effects on important physiological functions, ranging from development and growth to metabolism regulation, by interacting with specific nuclear or cytosolic receptors. Extranuclear or nongenomic effects of thyroid hormones are mediated by plasma membrane or cytoplasmic receptors, mainly by αvβ3 integrin, and are independent of protein synthesis. A wide variety of nongenomic effects have now been recognized to be elicited through the binding of thyroid hormones to this receptor, which is mainly involved in angiogenesis, as well as in cell cancer proliferation. Several signal transduction pathways are modulated by thyroid hormone binding to αvβ3 integrin: protein kinase C, protein kinase A, Src, or mitogen-activated kinases. Thyroid hormone-activated nongenomic effects are also involved in the regulation of Na+ -dependent transport systems, such as glucose uptake, Na+ /K+ -ATPase, Na+ /H+ exchanger, and amino acid transport System A. Of note, the modulation of these transport systems is cell-type and developmental stage-dependent. In particular, dysregulation of Na+ /K+ -ATPase activity is involved in several pathological situations, from viral infection to cancer. Therefore, this transport system represents a promising pharmacological tool in these pathologies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2022 Incerpi, Gionfra, De Luca, Candelotti, De Vito, Percario, Leone, Gnocchi, Rossi, Caruso, Scapin, Davis, Lin, Affabris and Pedersen.)- Published
- 2022
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39. Heteronemin and tetrac derivatives suppress non-small cell lung cancer growth via ERK1/2 inhibition.
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Chung CC, Huang TY, Chu HR, De Luca R, Candelotti E, Huang CH, Yang YSH, Incerpi S, Pedersen JZ, Lin CY, Huang HM, Lee SY, Li ZL, ChangOu CA, Li WS, Davis PJ, Lin HY, Whang-Peng J, and Wang K
- Subjects
- Antineoplastic Agents pharmacology, Cell Line, Tumor, Drug Therapy, Combination, Extracellular Signal-Regulated MAP Kinases genetics, Gene Expression Regulation, Neoplastic drug effects, Humans, Thyroxine pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Extracellular Signal-Regulated MAP Kinases metabolism, Lung Neoplasms drug therapy, Terpenes pharmacology, Thyroxine analogs & derivatives
- Abstract
The most common cancer, lung cancer, causes deaths worldwide. Most lung cancer patients have non-small cell lung carcinomas (NSCLCs) with a poor prognosis. The chemotherapies frequently cause resistance therefore search for new effective drugs for NSCLC patients is an urgent and essential issue. Deaminated thyroxine, tetraiodothyroacetic acid (tetrac), and its nano-analogue (NDAT) exhibit antiproliferative properties in several types of cancers. On the other hand, the most abundant secondary metabolite in the sponge Hippospongia sp., heteronemin, shows effective cytotoxic activity against different types of cancer cells. In the current study, we investigated the anticancer effects of heteronemin against two NSCLC cell lines, A549 and H1299 cells in vitro. Combined treatment with heteronemin and tetrac derivatives synergistically inhibited cancer cell growth and significantly modulated the ERK1/2 and STAT3 pathways in A549 cells but only ERK1/2 in H1299 cells. The combination treatments induce apoptosis via the caspases pathway in A549 cells but promote cell cycle arrest via CCND1 and PCNA inhibition in H1299 cells. In summary, these results suggest that combined treatment with heteronemin and tetrac derivatives could suppress signal transduction pathways essential for NSCLC cell growth. The synergetic effects can be used potentially as a therapeutic procedure for NSCLC patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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40. Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment.
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Caruso F, Pedersen JZ, Incerpi S, Kaur S, Belli S, Florea RM, and Rossi M
- Subjects
- Anti-Inflammatory Agents chemistry, COVID-19 metabolism, Caspase 1 chemistry, Caspase 1 metabolism, Caspase Inhibitors chemistry, Colchicine chemistry, Colchicine pharmacology, Coronavirus 3C Proteases antagonists & inhibitors, Coronavirus 3C Proteases chemistry, Coronavirus 3C Proteases metabolism, Dexamethasone pharmacology, Humans, Models, Molecular, Molecular Docking Simulation, Pentacyclic Triterpenes pharmacology, Protein Interaction Domains and Motifs, Raloxifene Hydrochloride chemistry, Raloxifene Hydrochloride pharmacology, Viral Protease Inhibitors chemistry, Viral Protease Inhibitors pharmacology, Anti-Inflammatory Agents pharmacology, Caspase 1 drug effects, Caspase Inhibitors pharmacology, Coronavirus 3C Proteases drug effects, COVID-19 Drug Treatment
- Abstract
The inflammatory protease caspase-1 is associated with the release of cytokines. An excessive number of cytokines (a "cytokine storm") is a dangerous consequence of COVID-19 infection and has been indicated as being among the causes of death by COVID-19. The anti-inflammatory drug colchicine (which is reported in the literature to be a caspase-1 inhibitor) and the corticosteroid drugs, dexamethasone and methylprednisolone, are among the most effective active compounds for COVID-19 treatment. The SERM raloxifene has also been used as a repurposed drug in COVID-19 therapy. In this study, inhibition of caspase-1 by these four compounds was analyzed using computational methods. Our aim was to see if the inhibition of caspase-1, an important biomolecule in the inflammatory response that triggers cytokine release, could shed light on how these drugs help to alleviate excessive cytokine production. We also measured the antioxidant activities of dexamethasone and colchicine when scavenging the superoxide radical using cyclic voltammetry methods. The experimental findings are associated with caspase-1 active site affinity towards these compounds. In evaluating our computational and experimental results, we here formulate a mechanism for caspase-1 inhibition by these drugs, which involves the active site amino acid Cys285 residue and is mediated by a transfer of protons, involving His237 and Ser339. It is proposed that the molecular moiety targeted by all of these drugs is a carbonyl group which establishes a S(Cys285)-C(carbonyl) covalent bond.
- Published
- 2022
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41. Evaluation of the Free Radical Scavenging Activities of Ellagic Acid and Ellagic Acid Peracetate by EPR Spectrometry.
- Author
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Kumar A, Kaushik P, Incerpi S, Pedersen JZ, Goel S, Prasad AK, Rohil V, Parmar VS, Saso L, and Len C
- Subjects
- Animals, Rats, Electron Spin Resonance Spectroscopy methods, Reactive Oxygen Species metabolism, Microsomes, Liver metabolism, Cell Line, Myoblasts metabolism, Myoblasts drug effects, Kinetics, Ellagic Acid pharmacology, Ellagic Acid chemistry, Ellagic Acid metabolism, Lipid Peroxidation drug effects, Free Radical Scavengers chemistry, Free Radical Scavengers pharmacology
- Abstract
The purpose of this study was to examine the free radical scavenging and antioxidant activities of ellagic acid (EA) and ellagic acid peracetate (EAPA) by measuring their reactions with the radicals, 2,2-diphenyl-1-picrylhydrazyl and galvinoxyl using EPR spectroscopy. We have also evaluated the influence of EA and EAPA on the ROS production in L-6 myoblasts and rat liver microsomal lipid peroxidation catalyzed by NADPH. The results obtained clearly indicated that EA has tremendous ability to scavenge free radicals, even at concentration of 1 µM. Interestingly even in the absence of esterase, EAPA, the acetylated product of EA, was also found to be a good scavenger but at a relatively slower rate. Kinetic studies revealed that both EA and EAPA have ability to scavenge free radicals at the concentrations of 1 µM over extended periods of time. In cellular systems, EA and EAPA were found to have similar potentials for the inhibition of ROS production in L-6 myoblasts and NADPH-dependent catalyzed microsomal lipid peroxidation.
- Published
- 2021
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42. Nano-Strategies Targeting the Integrin αvβ3 Network for Cancer Therapy.
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Cheng TM, Chang WJ, Chu HY, De Luca R, Pedersen JZ, Incerpi S, Li ZL, Shih YJ, Lin HY, Wang K, and Whang-Peng J
- Subjects
- Animals, Humans, Molecular Targeted Therapy, Nanoparticles chemistry, Signal Transduction, Integrin alphaVbeta3 metabolism, Nanomedicine, Neoplasms therapy
- Abstract
Integrin αvβ3, a cell surface receptor, participates in signaling transduction pathways in cancer cell proliferation and metastasis. Several ligands bind to integrin αvβ3 to regulate proliferation and metastasis in cancer cells. Crosstalk between the integrin and other signal transduction pathways also plays an important role in modulating cancer proliferation. Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) activates the downstream integrin FAK to stimulate biological activities including cancer proliferation and metastasis. Blockage of signals related to integrin αvβ3 was shown to be a promising target for cancer therapies. 3,3',5,5'-tetraiodothyroacetic acid (tetrac) completely binds to the integrin with the thyroid hormone to suppress cancer proliferation. The (E)-stilbene analog, resveratrol, also binds to integrin αvβ3 to inhibit cancer growth. Recently, nanotechnologies have been used in the biomedical field for detection and therapeutic purposes. In the current review, we show and evaluate the potentiation of the nanomaterial carrier RGD peptide, derivatives of PLGA-tetrac (NDAT), and nanoresveratrol targeting integrin αvβ3 in cancer therapies.
- Published
- 2021
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43. Inhibition by Thyroid Hormones of Cell Migration Activated by IGF-1 and MCP-1 in THP-1 Monocytes: Focus on Signal Transduction Events Proximal to Integrin αvβ3.
- Author
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Candelotti E, De Luca R, Megna R, Maiolo M, De Vito P, Gionfra F, Percario ZA, Borgatti M, Gambari R, Davis PJ, Lin HY, Polticelli F, Persichini T, Colasanti M, Affabris E, Pedersen JZ, and Incerpi S
- Abstract
Interaction between thyroid hormones and the immune system is reported in the literature. Thyroid hormones, thyroxine, T
4 , but also T3 , act non-genomically through mechanisms that involve a plasma membrane receptor αvβ3 integrin, a co-receptor for insulin-like growth factor-1 (IGF-1). Previous data from our laboratory show a crosstalk between thyroid hormones and IGF-1 because thyroid hormones inhibit the IGF-1-stimulated glucose uptake and cell proliferation in L-6 myoblasts, and the effects are mediated by integrin αvβ3. IGF-1 also behaves as a chemokine, being an important factor for tissue regeneration after damage. In the present study, using THP-1 human leukemic monocytes, expressing αvβ3 integrin in their cell membrane, we focused on the crosstalk between thyroid hormones and either IGF-1 or monocyte chemoattractant protein-1 (MCP-1), studying cell migration and proliferation stimulated by the two chemokines, and the role of αvβ3 integrin, using inhibitors of αvβ3 integrin and downstream pathways. Our results show that IGF-1 is a potent chemoattractant in THP-1 monocytes, stimulating cell migration, and thyroid hormone inhibits the effect through αvβ3 integrin. Thyroid hormone also inhibits IGF-1-stimulated cell proliferation through αvβ3 integrin, an example of a crosstalk between genomic and non-genomic effects. We also studied the effects of thyroid hormone on cell migration and proliferation induced by MCP-1, together with the pathways involved, by a pharmacological approach and docking simulation. Our findings show a different downstream signaling for IGF-1 and MCP-1 in THP-1 monocytes mediated by the plasma membrane receptor of thyroid hormones, integrin αvβ3., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors RDL., (Copyright © 2021 Candelotti, De Luca, Megna, Maiolo, De Vito, Gionfra, Percario, Borgatti, Gambari, Davis, Lin, Polticelli, Persichini, Colasanti, Affabris, Pedersen and Incerpi.)- Published
- 2021
- Full Text
- View/download PDF
44. Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome.
- Author
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De Luca R, Davis PJ, Lin HY, Gionfra F, Percario ZA, Affabris E, Pedersen JZ, Marchese C, Trivedi P, Anastasiadou E, Negro R, and Incerpi S
- Abstract
The interdependence between thyroid hormones (THs), namely, thyroxine and triiodothyronine, and immune system is nowadays well-recognized, although not yet fully explored. Synthesis, conversion to a bioactive form, and release of THs in the circulation are events tightly supervised by the hypothalamic-pituitary-thyroid (HPT) axis. Newly synthesized THs induce leukocyte proliferation, migration, release of cytokines, and antibody production, triggering an immune response against either sterile or microbial insults. However, chronic patho-physiological alterations of the immune system, such as infection and inflammation, affect HPT axis and, as a direct consequence, THs mechanism of action. Herein, we revise the bidirectional crosstalk between THs and immune cells, required for the proper immune system feedback response among diverse circumstances. Available circulating THs do traffic in two distinct ways depending on the metabolic condition. Mechanistically, internalized THs form a stable complex with their specific receptors, which, upon direct or indirect binding to DNA, triggers a genomic response by activating transcriptional factors, such as those belonging to the Wnt/β-catenin pathway. Alternatively, THs engage integrin αvβ3 receptor on cell membrane and trigger a non-genomic response, which can also signal to the nucleus. In addition, we highlight THs-dependent inflammasome complex modulation and describe new crucial pathways involved in microRNA regulation by THs, in physiological and patho-physiological conditions, which modify the HPT axis and THs performances. Finally, we focus on the non-thyroidal illness syndrome in which the HPT axis is altered and, in turn, affects circulating levels of active THs as reported in viral infections, particularly in immunocompromised patients infected with human immunodeficiency virus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 De Luca, Davis, Lin, Gionfra, Percario, Affabris, Pedersen, Marchese, Trivedi, Anastasiadou, Negro and Incerpi.)
- Published
- 2021
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45. Antioxidant and Biological Activities of Hydroxytyrosol and Homovanillic Alcohol Obtained from Olive Mill Wastewaters of Extra-Virgin Olive Oil Production.
- Author
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Ricelli A, Gionfra F, Percario Z, De Angelis M, Primitivo L, Bonfantini V, Antonioletti R, Bullitta SM, Saso L, Incerpi S, and Pedersen JZ
- Subjects
- Animals, Antioxidants chemistry, Cell Line, Cell Proliferation drug effects, Homovanillic Acid chemistry, Humans, Olea chemistry, Olive Oil chemistry, Phenylethyl Alcohol blood, Phenylethyl Alcohol isolation & purification, Plant Extracts chemistry, Rats, Reactive Oxygen Species metabolism, Waste Products analysis, Antioxidants isolation & purification, Homovanillic Acid isolation & purification, Phenylethyl Alcohol analogs & derivatives, Plant Extracts isolation & purification, Wastewater chemistry
- Abstract
Some constituents of the Mediterranean diet, such as extra-virgin olive oil (EVOO) contain substances such as hydroxytyrosol (HT) and its metabolite homovanillic alcohol (HA). HT has aroused much interest due to its antioxidant activity as a radical scavenger, whereas only a few studies have been made on the HA molecule. Both chemical synthesis and extraction techniques have been developed to obtain these molecules, with each method having its advantages and drawbacks. In this study, we report the use of tyrosol from olive mill wastewaters as a starting molecule to synthesize HT and HA, using a sustainable procedure characterized by high efficiency and low cost. The effects of HT and HA were evaluated on two cell lines, THP-1 human leukemic monocytes and L-6 myoblasts from rat skeletal muscle, after treating the cells with a radical generator. Both HT and HA efficiently inhibited ROS production. In particular, HT inhibited the proliferation of the THP-1 leukemic monocytes, while HA protected L-6 myoblasts from cytotoxicity.
- Published
- 2020
- Full Text
- View/download PDF
46. Computational studies reveal mechanism by which quinone derivatives can inhibit SARS-CoV-2. Study of embelin and two therapeutic compounds of interest, methyl prednisolone and dexamethasone.
- Author
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Caruso F, Rossi M, Pedersen JZ, and Incerpi S
- Subjects
- Benzoquinones pharmacology, Dexamethasone pharmacology, Drug Repositioning, Humans, Methylprednisolone pharmacology, Molecular Docking Simulation, Anti-Inflammatory Agents pharmacology, SARS-CoV-2 drug effects, COVID-19 Drug Treatment
- Abstract
Background: Quinones are reactive to proteins containing cysteine residues and the main protease in Covid-19 contains an active site that includes Cys145. Embelin, a quinone natural product, is known to have antiviral activity against influenza and hepatitis B. Preliminary studies by our group also indicate its ability to inhibit HSV-1 in cultured cells., Methods: Docking and DFT methods applied to the protease target., Results: a mechanism for this inhibition of the SARS-CoV-2 Mpro protease is described, specifically due to formation of a covalent bond between S(Cys145) and an embelin C(carbonyl). This is assisted by two protein amino acids (1) N(imidazole-His41) which is able to capture H[S(Cys145)] and (2) HN(His163), which donates a proton to embelin O(carbonyl) forming an OH moiety that results in inhibition of the viral protease. A similar process is also seen with the anti-inflammatory drugs methyl prednisolone and dexamethasone, used for Covid-19 patients. Methyl prednisolone and dexamethasone are methide quinones, and possess only one carbonyl moiety, instead of two for embelin. Additional consideration was given to another natural product, emodin, recently patented against Covid-19, as well as some therapeutic quinones, vitamin K, suspected to be involved in Covid-19 action, and coenzyme Q10. All show structural similarities with embelin, dexamethasone and methyl prednisolone results., Conclusions: Our data on embelin and related quinones indicate that these natural compounds may represent a feasible, strategic tool against Covid-19., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
47. Combined Treatment of Heteronemin and Tetrac Induces Antiproliferation in Oral Cancer Cells.
- Author
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Huang CH, Huang TY, Chang WJ, Pan YS, Chu HR, Li ZL, Unson S, Chin YT, Lin CY, Huang HM, Hsiung CN, Gionfra F, De Vito P, Pedersen JZ, Incerpi S, Chen YR, Lee SY, Lin HY, Davis PJ, Whang-Peng J, and Wang K
- Subjects
- Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Cell Line, Tumor, Gene Expression Regulation, Neoplastic drug effects, Humans, Terpenes administration & dosage, Thyroxine administration & dosage, Thyroxine pharmacology, Carcinoma drug therapy, Cell Proliferation drug effects, Gingival Neoplasms drug therapy, Terpenes pharmacology, Thyroxine analogs & derivatives
- Abstract
Background: Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative effect in cancer cells. In addition, heteronemin has been shown to inhibit p53 expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activates p53 and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells., Methods: We investigated the antiproliferative effects by Cell Counting Kit-8 and flow cytometry. The signal transduction pathway was measured by Western blotting analyses. Quantitative PCR was used to evaluate gene expression regulated by heteronemin, 3,3',5,5'-tetraiodothyroacetic acid (tetrac), or their combined treatment in oral cancer cells., Results: Heteronemin inhibited not only expression of proliferative genes and Homo Sapiens Thrombospondin 1 ( THBS-1 ) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increased TGF-β1 expression in SCC-25 cells. Tetrac suppressed expression of THBS-1 but not p53 expression in both cancer cell lines. Furthermore, the synergistic effect of tetrac and heteronemin inhibited ERK1/2 activation and heteronemin also blocked STAT3 signaling. Combined treatment increased p53 protein and p53 activation accumulation although heteronemin inhibited p53 expression in both cancer cell lines. The combined treatment induced antiproliferation synergistically more than a single agent., Conclusions: Both heteronemin and tetrac inhibited ERK1/2 activation and increased p53 phosphorylation. They also inhibited THBS-1 expression. Moreover, tetrac suppressed TGF-β expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.
- Published
- 2020
- Full Text
- View/download PDF
48. Antioxidant Properties of Embelin in Cell Culture. Electrochemistry and Theoretical Mechanism of Scavenging. Potential Scavenging of Superoxide Radical through the Cell Membrane.
- Author
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Caruso F, Rossi M, Kaur S, Garcia-Villar E, Molasky N, Belli S, Sitek JD, Gionfra F, Pedersen JZ, and Incerpi S
- Abstract
Embelin, a plant natural product found in Lysimachia punctata (Primulaceae), and Embelia ribes Burm (Myrsinaceae) fruit, possesses interesting biological and pharmacological properties. It is a unique chemical species as it includes both quinone and hydroquinone functional groups plus a long hydrophobic tail. By using hydrodynamic voltammetry, which generates the superoxide radical in situ, we show an unusual scavenging capability by embelin. Embelin as a scavenger of superoxide is stronger than the common food additive antioxidant 2,6-bis(1,1-dimethylethyl)-4-20 methylphenol, (butylated hydroxytoluene, BHT). In fact, embelin is even able to completely abolish the superoxide radical in the voltaic cell. Computational results indicate that two different types of embelin scavenging actions may be involved, initially through π-π interaction and followed by proton capture in the cell. A related mechanism describes embelin's ability to circumvent superoxide leaking by transforming the anion radical into molecular oxygen. In order to confirm its antioxidant properties, its biological activity was tested in a study carried out in THP-1 human leukemic monocytes and BV-2 mice microglia. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, proliferation curves and antioxidant activity by the use of a fluorescent probe showed good antioxidant properties at 24 h. This suggests that embelin's long alkyl C10 tail may be useful for cell membrane insertion which stimulates the antioxidant defense system, and cytoprotection in microglia. In conclusion, embelin could be an interesting pharmacological tool able to decrease the damage associated with metabolic and neurodegenerative diseases.
- Published
- 2020
- Full Text
- View/download PDF
49. The Role of Thyroid Hormones in Hepatocyte Proliferation and Liver Cancer.
- Author
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Gionfra F, De Vito P, Pallottini V, Lin HY, Davis PJ, Pedersen JZ, and Incerpi S
- Abstract
Thyroid hormones T3 and T4 (thyroxine) control a wide variety of effects related to development, differentiation, growth and metabolism, through their interaction with nuclear receptors. But thyroid hormones also produce non-genomic effects that typically start at the plasma membrane and are mediated mainly by integrin αvβ3, although other receptors such as TRα and TRβ are also able to elicit non-genomic responses. In the liver, the effects of thyroid hormones appear to be particularly important. The liver is able to regenerate, but it is subject to pathologies that may lead to cancer, such as fibrosis, cirrhosis, and non-alcoholic fatty liver disease. In addition, cancer cells undergo a reprogramming of their metabolism, resulting in drastic changes such as aerobic glycolysis instead of oxidative phosphorylation. As a consequence, the pyruvate kinase isoform M2, the rate-limiting enzyme of glycolysis, is dysregulated, and this is considered an important factor in tumorigenesis. Redox equilibrium is also important, in fact cancer cells give rise to the production of more reactive oxygen species (ROS) than normal cells. This increase may favor the survival and propagation of cancer cells. We evaluate the possible mechanisms involving the plasma membrane receptor integrin αvβ3 that may lead to cancer progression. Studying diseases that affect the liver and their experimental models may help to unravel the cellular pathways mediated by integrin αvβ3 that can lead to liver cancer. Inhibitors of integrin αvβ3 might represent a future therapeutic tool against liver cancer. We also include information on the possible role of exosomes in liver cancer, as well as on recent strategies such as organoids and spheroids, which may provide a new tool for research, drug discovery, and personalized medicine.
- Published
- 2019
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50. Corrigendum: Tetrac and NDAT Induce Anti-proliferation via Integrin αvβ3 in Colorectal Cancers With Different K-RAS Status.
- Author
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Chin YT, He ZR, Chen CL, Chu HC, Ho Y, Su PY, Yang YSH, Wang K, Shih YJ, Chen YR, Pedersen JZ, Incerpi S, Nana AW, Tang HY, Lin HY, Mousa SA, Davis PJ, and Whang-Peng J
- Abstract
[This corrects the article DOI: 10.3389/fendo.2019.00130.].
- Published
- 2019
- Full Text
- View/download PDF
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