20 results on '"Ilaria M. Marone"'
Search Results
2. Data from TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione
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Silvia Benemei, Pierangelo Geppetti, Mariarosaria Di Tommaso, Gloriano Moneti, Alessandro Terreni, Tommaso Susini, Alyn H. Morice, Laura R. Sadofsky, Ilaria M. Marone, Simone Li Puma, Elisabetta Coppi, Camilla Fusi, Romina Nassini, Serena Materazzi, Raquel Tonello, and Francesco De Logu
- Abstract
Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS. Cancer Res; 76(23); 7024–35. ©2016 AACR.
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- 2023
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3. Supplementary Figures from TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione
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Silvia Benemei, Pierangelo Geppetti, Mariarosaria Di Tommaso, Gloriano Moneti, Alessandro Terreni, Tommaso Susini, Alyn H. Morice, Laura R. Sadofsky, Ilaria M. Marone, Simone Li Puma, Elisabetta Coppi, Camilla Fusi, Romina Nassini, Serena Materazzi, Raquel Tonello, and Francesco De Logu
- Abstract
Supplementary Figure 1 shows the chemical structure of exemestane, androstenedione and testosterone, and responses (calcium mobilization or currents) evoked by androstenedione and other steroid hormones in cells that express the native or recombinant (including a mutated form) TRPA1 channel. Supplementary Figure 2 shows the inhibitory effect of the ROS scavenger, alpha lipoic acid, on the mechanical allodynia induced by intragastric administration of letrozole. Supplementary Figure 3 shows that the combination of per se ineffective doses of androstenedione, letrozole or H202 is able to evoke mechanical allodynia. Supplementary Figure 4 shows the ability of the TRPA1 antagonist, HC-030031, and TRPV1 antagonist, capsazepine, to modulate the responses (mechanical allodynia, grip strength reduction) evoked by buthionine sulfoximine and androstenedione.
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- 2023
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4. Oxidative stress mediates thalidomide-induced pain by targeting peripheral TRPA1 and central TRPV4
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Mustafa Titiz, Francesco De Logu, Gabriela Trevisan, Elisabetta Coppi, Ilaria M. Marone, Serena Materazzi, Gaetano De Siena, Diéssica Padilha Dalenogare, Matilde Marini, Simone Li Puma, Pierangelo Geppetti, Daniel Souza Monteiro de Araujo, Lorenzo Landini, and Romina Nassini
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TRPV4 ,Male ,Physiology ,TRPV1 ,Pain ,TRPV Cation Channels ,Plant Science ,Biology ,Pharmacology ,medicine.disease_cause ,TRPA1 ,General Biochemistry, Genetics and Molecular Biology ,Rats, Sprague-Dawley ,Chemotherapeutic-induced peripheral neuropathy ,Oxidative stress ,Thalidomide ,03 medical and health sciences ,Transient receptor potential channel ,Mice ,0302 clinical medicine ,Structural Biology ,medicine ,Animals ,TRPA1 Cation Channel ,lcsh:QH301-705.5 ,Ecology, Evolution, Behavior and Systematics ,Cell Biology ,medicine.disease ,Pomalidomide ,3. Good health ,Rats ,Mice, Inbred C57BL ,Peripheral neuropathy ,Allodynia ,lcsh:Biology (General) ,Hyperalgesia ,030220 oncology & carcinogenesis ,medicine.symptom ,General Agricultural and Biological Sciences ,030217 neurology & neurosurgery ,psychological phenomena and processes ,Developmental Biology ,Biotechnology ,medicine.drug ,Research Article - Abstract
Background The mechanism underlying the pain symptoms associated with chemotherapeutic-induced peripheral neuropathy (CIPN) is poorly understood. Transient receptor potential ankyrin 1 (TRPA1), TRP vanilloid 4 (TRPV4), TRPV1, and oxidative stress have been implicated in several rodent models of CIPN-evoked allodynia. Thalidomide causes a painful CIPN in patients via an unknown mechanism. Surprisingly, the pathway responsible for such proalgesic response has not yet been investigated in animal models. Results Here, we reveal that a single systemic administration of thalidomide and its derivatives, lenalidomide and pomalidomide, elicits prolonged (~ 35 days) mechanical and cold hypersensitivity in C57BL/6J mouse hind paw. Pharmacological antagonism or genetic deletion studies indicated that both TRPA1 and TRPV4, but not TRPV1, contribute to mechanical allodynia, whereas cold hypersensitivity was entirely due to TRPA1. Thalidomide per se did not stimulate recombinant and constitutive TRPA1 and TRPV4 channels in vitro, which, however, were activated by the oxidative stress byproduct, hydrogen peroxide. Systemic treatment with an antioxidant attenuated mechanical and cold hypersensitivity, and the increase in oxidative stress in hind paw, sciatic nerve, and lumbar spinal cord produced by thalidomide. Notably, central (intrathecal) or peripheral (intraplantar) treatments with channel antagonists or an antioxidant revealed that oxidative stress-dependent activation of peripheral TRPA1 mediates cold allodynia and part of mechanical allodynia. However, oxidative stress-induced activation of central TRPV4 mediated the residual TRPA1-resistant component of mechanical allodynia. Conclusions Targeting of peripheral TRPA1 and central TRPV4 may be required to attenuate pain associated with CIPN elicited by thalidomide and related drugs.
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- 2020
5. Transient receptor potential ankyrin 1 contributes to somatic pain hypersensitivity in experimental colitis
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Romina Nassini, Peter Holzer, Elisabetta Coppi, Francesco De Logu, Serena Materazzi, Simone Li Puma, Pierangelo Geppetti, Piyush Jain, Camilla Fusi, Ilaria M. Marone, and Duccio Rossi Degl'Innocenti
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Agonist ,Male ,medicine.medical_specialty ,Somatic cell ,medicine.drug_class ,Pain ,lcsh:Medicine ,Inflammation ,Article ,Inflammatory bowel disease ,Nociceptive Pain ,Trigeminal ganglion ,Transient receptor potential channel ,Mice ,Dorsal root ganglion ,Isothiocyanates ,Internal medicine ,Ganglia, Spinal ,medicine ,Animals ,Colitis ,lcsh:Science ,Evoked Potentials ,TRPA1 Cation Channel ,Mice, Knockout ,Multidisciplinary ,business.industry ,Dextran Sulfate ,lcsh:R ,food and beverages ,Digestive signs and symptoms ,medicine.disease ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,Trigeminal Ganglion ,Purines ,Nociceptor ,TRPA1, pain ,Acetanilides ,lcsh:Q ,Stress, Mechanical ,medicine.symptom ,business ,psychological phenomena and processes - Abstract
Pain evoked by visceral inflammation is often ‘referred’ to the somatic level. Transient receptor potential ankyrin 1 (TRPA1) has been reported to contribute to visceral pain-like behavior in dextran sulfate sodium (DSS)-evoked colitis. However, the role of TRPA1 in somatic component of hypersensitivity due to visceral inflammation is unknown. The present study investigated the role of TRPA1 in colitis-evoked mechanical hypersensitivity at the somatic level. Colitis was induced in mice by adding DSS to drinking water for one week. Control and DSS-treated mice were tested for various parameters of colitis as well as mechanical pain sensitivity in abdominal and facial regions. DSS treatment caused mechanical hypersensitivity in the abdominal and facial skin. Pharmacological blockade or genetic deletion of TRPA1 prevented the colitis-associated mechanical hypersensitivity in the abdominal and facial skin areas although the severity of colitis remained unaltered. DSS treatment increased expression of TRPA1 mRNA in cultured dorsal root ganglion (DRG) neurons, but not trigeminal ganglion neurons, and selectively enhanced currents evoked by the TRPA1 agonist, allyl isothiocyanate, in cultured DRG neurons. Our findings indicate that the TRPA1 channel contributes to colitis-associated mechanical hypersensitivity in somatic tissues, an effect associated with upregulation of TRPA1 expression and responsiveness in DRG nociceptors.
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- 2020
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6. Spectrum of ASXL1 mutations in primary myelofibrosis: prognostic impact of the ASXL1 p.G646Wfs*12 mutation
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Mario Cazzola, Alessandro M. Vannucchi, Chiara Paoli, Rossella Manfredini, Paola Guglielmelli, Elisa Rumi, Francesco Mannelli, Annalisa Pacilli, Sara Fiaccabrino, Giada Rotunno, Giada Brogi, Giovanni Barosi, Benedetta Sordi, Francesca Gesullo, Carmela Mannarelli, and Ilaria M. Marone
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0301 basic medicine ,ASXL1 gene ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,03 medical and health sciences ,Adolescent ,Adult ,Aged ,Aged, 80 and over ,Female ,Humans ,Leukemia ,Male ,Middle Aged ,Mutation ,Primary Myelofibrosis ,Prognosis ,Repressor Proteins ,Young Adult ,030104 developmental biology ,0302 clinical medicine ,Mutation (genetic algorithm) ,medicine ,Cancer research ,In patient ,Myelofibrosis ,business ,030215 immunology - Abstract
TO THE EDITOR: The discovery of prognostically informative mutations in patients with primary myelofibrosis (PMF)[1][1] prompted the development of mutation-enhanced risk scores.[2][2][⇓][3][⇓][4][⇓][5]-[6][6] Among these mutations, those in ASXL1 are invariably associated with adverse
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- 2019
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7. TRPA1 mediates the antinociceptive properties of the constituent of Crocus sativus L., safranal
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Riccardo Patacchini, Pierangelo Geppetti, Ilaria M. Marone, Romina Nassini, Simone Li Puma, Viola Seravalli, Francesco De Logu, Sergio J. Macedo, Elisabetta Coppi, Serena Materazzi, and Lorenzo Landini
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Nociception ,0301 basic medicine ,calcitonin gene‐related peptide ,Pharmacology ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Dorsal root ganglion ,Isothiocyanates ,Ganglia, Spinal ,pain ,TRPA1 Cation Channel ,Neurons ,Analgesics ,neurogenic inflammation ,Chemistry ,food and beverages ,safranal ,calcitonin gene-related peptide ,transient receptor potential ankyrin 1 ,Safranal ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Nociceptor ,Molecular Medicine ,Original Article ,Sesquiterpenes ,psychological phenomena and processes ,Agonist ,medicine.drug_class ,TRPV1 ,TRPV Cation Channels ,Calcitonin gene-related peptide ,Partial agonist ,Cell Line ,03 medical and health sciences ,Cyclohexenes ,medicine ,Animals ,Humans ,Terpenes ,Original Articles ,Cell Biology ,Crocus ,Mice, Inbred C57BL ,HEK293 Cells ,030104 developmental biology ,nervous system ,Calcium Channels - Abstract
Safranal, contained in Crocus sativus L., exerts anti‐inflammatory and analgesic effects. However, the underlying mechanisms for such effects are poorly understood. We explored whether safranal targets the transient receptor potential ankyrin 1 (TRPA1) channel, which in nociceptors mediates pain signals. Safranal by binding to specific cysteine/lysine residues, stimulates TRPA1, but not the TRP vanilloid 1 and 4 channels (TRPV1 and TRPV4), evoking calcium responses and currents in human cells and rat and mouse dorsal root ganglion (DRG) neurons. Genetic deletion or pharmacological blockade of TRPA1 attenuated safranal‐evoked release of calcitonin gene‐related peptide (CGRP) from rat and mouse dorsal spinal cord, and acute nociception in mice. Safranal contracted rat urinary bladder isolated strips in a TRPA1‐dependent manner, behaving as a partial agonist. After exposure to safranal the ability of allyl isothiocyanate (TRPA1 agonist), but not that of capsaicin (TRPV1 agonist) or GSK1016790A (TRPV4 agonist), to evoke currents in DRG neurons, contraction of urinary bladder strips and CGRP release from spinal cord slices in rats, and acute nociception in mice underwent desensitization. As previously shown for other herbal extracts, including petasites or parthenolide, safranal might exert analgesic properties by partial agonism and selective desensitization of the TRPA1 channel.
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- 2019
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8. Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice
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Daniel Souza Monteiro de Araujo, Silvia Benemei, Muryel De Carvalho Goncalves, Juliano Ferreira, Pierangelo Geppetti, Francesco De Logu, Gabriela Trevisan, Serena Materazzi, Simone Li Puma, Daniele Nosi, Romina Nassini, Ilaria M. Marone, Nigel W. Bunnett, Riccardo Patacchini, and Duccio Rossi Degl'Innocenti
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0301 basic medicine ,Male ,Science ,General Physics and Astronomy ,Schwann cell ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Transient receptor potential channel ,Mice ,0302 clinical medicine ,medicine ,Macrophage ,Animals ,Humans ,lcsh:Science ,TRPA1 Cation Channel ,Neuroinflammation ,Multidisciplinary ,Chemistry ,Macrophages ,food and beverages ,General Chemistry ,biochemical phenomena, metabolism, and nutrition ,Sciatic Nerve ,Cell biology ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Allodynia ,medicine.anatomical_structure ,nervous system ,NOX1 ,NADPH Oxidase 2 ,Schwann cell, TRPA1, neuroinflammation, neuropathic pain ,Nociceptor ,NADPH Oxidase 1 ,Neuralgia ,lcsh:Q ,Sciatic nerve ,Schwann Cells ,medicine.symptom ,030217 neurology & neurosurgery ,psychological phenomena and processes - Abstract
It is known that transient receptor potential ankyrin 1 (TRPA1) channels, expressed by nociceptors, contribute to neuropathic pain. Here we show that TRPA1 is also expressed in Schwann cells. We found that in mice with partial sciatic nerve ligation, TRPA1 silencing in nociceptors attenuated mechanical allodynia, without affecting macrophage infiltration and oxidative stress, whereas TRPA1 silencing in Schwann cells reduced both allodynia and neuroinflammation. Activation of Schwann cell TRPA1 evoked NADPH oxidase 1 (NOX1)-dependent H2O2 release, and silencing or blocking Schwann cell NOX1 attenuated nerve injury-induced macrophage infiltration, oxidative stress and allodynia. Furthermore, the NOX2-dependent oxidative burst, produced by macrophages recruited to the perineural space activated the TRPA1–NOX1 pathway in Schwann cells, but not TRPA1 in nociceptors. Schwann cell TRPA1 generates a spatially constrained gradient of oxidative stress, which maintains macrophage infiltration to the injured nerve, and sends paracrine signals to activate TRPA1 of ensheathed nociceptors to sustain mechanical allodynia., Following peripheral nerve injury, influx of immune cells to the site may contribute to the development of chronic pain. Here the authors show that TRPA1 is expressed on Schwann cells and contributes to immune cell influx in a mouse model of neuropathic pain.
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- 2017
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9. The anti-migraine component of butterbur extracts, isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel
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Francesco De Logu, Wolfgang Liedtke, Ilaria M. Marone, Serena Materazzi, Pollastro Federica, Romina Nassini, Filippo Ugolini, Pierangelo Geppetti, Silvia Benemei, Simone Li Puma, Giovanni Appendino, and Elisabetta Coppi
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0301 basic medicine ,Pharmacology ,Agonist ,Neurogenic inflammation ,medicine.drug_class ,Chemistry ,TRPV1 ,Calcitonin gene-related peptide ,03 medical and health sciences ,Trigeminal ganglion ,Transient receptor potential channel ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Capsaicin ,medicine ,Nociceptor ,030217 neurology & neurosurgery - Abstract
Background and Purpose The mechanism of the antimigraine action of butterbur [Petasites hybridus (L.) Gaertn.] is unknown. Here, we investigated the ability of isopetasin, a major butterbur constituent, to specifically target the transient receptor ankyrin 1 (TRPA1) channel and to affect functional responses relevant to migraine. Experimental Approach Single cell calcium imaging and patch-clamp recordings in human and rodent TRPA1-expressing cells, neurogenic motor responses in isolated rat/mouse urinary bladder, release of calcitonin gene-related peptide (CGRP) from mouse spinal cord in vitro, and facial rubbing in mice and meningeal blood flow in rat were examined. Key Results Isopetasin produced (i) calcium responses and currents in rat/mouse trigeminal ganglion (TG) neurons and in cells expressing the human TRPA1, (ii) substance P-mediated contractions of isolated rat urinary bladders and (iii) CGRP release from mouse dorsal spinal cord, responses that were selectively abolished by TRPA1 genetic deletion/pharmacological antagonism. Pre-exposure to isopetasin produced marked desensitisation of allyl isothiocyanate (AITC, TRPA1 agonist)- or capsaicin (TRPV1 agonist)-evoked currents in rat TG neurons, contractions of rat or mouse urinary bladder and CGRP release from mouse central terminals of primary sensory neurons. Repeated intragastric administration of isopetasin attenuated mouse facial rubbing, evoked by local AITC or capsaicin, and dilation of rat meningeal arteries by acrolein or ethanol (TRPA1 and TRPV1 agonists, respectively). Conclusion and Implications TRPA1 agonism by isopetasin results in excitation of neuropeptide-containing nociceptors that is followed by remarkable heterologous neuronal desensitisation. Such attenuation in pain and neurogenic inflammation may account for the antimigraine action of butterbur.
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- 2017
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10. Italian survey on clinical practice in myeloproliferative neoplasms. A GIMEMA Myeloproliferative Neoplasms Working Party initiative
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Lara Mannelli, Bruno Martino, Francesco Mannelli, Tiziano Barbui, Guido Finazzi, Sergio Amadori, Giacomo Coltro, Chiara Paoli, Paola Fazi, Valerio De Stefano, Benedetta Sordi, Sergio Siragusa, Ilaria M. Marone, Massimo Breccia, Giuseppe Gaetano Loscocco, Francesco Passamonti, Duccio Fantoni, Francesca Palandri, Alessandra Iurlo, Paola Guglielmelli, Rosalba Cucci, Francesco Albano, Alessandro M. Vannucchi, Marco Vignetti, Loscocco G.G., Mannelli F., Guglielmelli P., Paoli C., Marone I., Cucci R., Coltro G., Sordi B., Albano F., Breccia M., De Stefano V., Finazzi G., Iurlo A., Martino B., Palandri F., Passamonti F., Siragusa S., Mannelli L., Fantoni D., Fazi P., Amadori S., Vignetti M., Barbui T., and Vannucchi A.M.
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medicine.medical_specialty ,Myeloproliferative Disorders ,business.industry ,Hematology ,Myeloproliferative neoplasm, surevy ,medicine.disease ,Clinical Practice ,Settore MED/15 - MALATTIE DEL SANGUE ,Italy ,Hematologic Neoplasms ,Surveys and Questionnaires ,Family medicine ,medicine ,Humans ,Myeloproliferative Neoplasms ,Guideline Adherence ,business ,Myeloproliferative neoplasm - Published
- 2019
11. TRPA1 Mediates Aromatase Inhibitor–Evoked Pain by the Aromatase Substrate Androstenedione
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Mariarosaria Di Tommaso, Camilla Fusi, Simone Li Puma, Alyn H. Morice, Pierangelo Geppetti, Romina Nassini, Ilaria M. Marone, Alessandro Terreni, Francesco De Logu, Laura R. Sadofsky, Serena Materazzi, Elisabetta Coppi, Tommaso Susini, Silvia Benemei, Raquel Tonello, and Gloriano Moneti
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,Transfection ,medicine.disease_cause ,Rats, Sprague-Dawley ,Mice ,03 medical and health sciences ,Transient receptor potential channel ,Transient Receptor Potential Channels ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Androstenedione ,Aromatase ,Receptor ,Aromatase inhibitor ,biology ,Aromatase Inhibitors ,business.industry ,Letrozole ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,business ,Oxidative stress ,Hormone ,medicine.drug - Abstract
Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS. Cancer Res; 76(23); 7024–35. ©2016 AACR.
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- 2016
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12. The peptide Phα1β, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice
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Muryel De Carvalho Goncalves, Juliano Ferreira, Pierangelo Geppetti, Francesco De Logu, Romina Nassini, Serena Materazzi, Marcus Vinicius Gomez, Raquel Tonello, Ilaria M. Marone, Elisabetta Coppi, Camilla Fusi, Silvia Benemei, and Celio J. Castro-Junior
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0301 basic medicine ,Pharmacology ,Agonist ,Voltage-dependent calcium channel ,medicine.drug_class ,TRPV1 ,03 medical and health sciences ,chemistry.chemical_compound ,Transient receptor potential channel ,030104 developmental biology ,0302 clinical medicine ,Nociception ,medicine.anatomical_structure ,chemistry ,Dorsal root ganglion ,Capsaicin ,Hyperalgesia ,medicine ,medicine.symptom ,psychological phenomena and processes ,030217 neurology & neurosurgery - Abstract
BACKGROUND AND PURPOSE Peptides from venomous animals have long been important tools for understanding pain mechanisms and for the discovery of pain treatments. Here, we hypothesized that Phα1β, a peptide purified from the armed spider Phoneutria nigriventer venom, produces analgesia by blocking the transient receptor potential ankyrin 1 (TRPA1) channel. EXPERIMENTAL APPROACH Cultured rat dorsal root ganglion (DRG) neurons, human IMR90 fibroblasts or HEK293 cells expressing the human TRPA1 (hTRPA1-HEK293), TRPV1 (hTRPV1-HEK293) or TRPV4 (hTRPV4-HEK293), were used for calcium imaging and electrophysiology. Pain-like responses induced by TRPA1, TRPV1 or TRPV4 agonists or by bortezomib were also investigated in mice. KEY RESULTS Phα1β selectively inhibited calcium responses and currents evoked by the TRPA1 agonist, allyl isothiocyanate (AITC), on hTRPA1-HEK293, IMR90 fibroblasts and DRG neurons. Phα1β did not affect calcium responses evoked by selective TRPV1 (capsaicin) or TRPV4 (GSK 1016790A) agonists on the various cell types. Intrathecal (i.t.) and intraplantar (i.pl.) administration of low doses of Phα1β (up to 300 pmol per paw) attenuated acute nociception and mechanical and cold hyperalgesia evoked by AITC (i.t or i.pl), without affecting responses produced by capsaicin or hypotonic solution. Notably, Phα1β abated the TRPA1-dependent neuropathic pain-like responses induced by bortezomib. Finally, in vitro and in vivo inhibition of TRPA1 by Phα1β was recapitulated by a recombinant version of the peptide, CTK 01512-2. CONCLUSIONS AND IMPLICATIONS Phα1β and CTK 01512-2 selectively target TRPA1, but not other TRP channels. This specific action underlines the potential of Phα1β and CTK 01512-2 for pain treatment.
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- 2016
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13. TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress
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Mateus Fortes Rossato, Romina Nassini, Juliano Ferreira, Ilaria M. Marone, Gaetano De Siena, Elisabetta Coppi, Pierangelo Geppetti, Silvia Benemei, Francesco De Logu, Gabriela Trevisan, Serena Materazzi, and Camilla Fusi
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Male ,0301 basic medicine ,Pharmacology ,Monocytes ,Mice ,03 medical and health sciences ,Infraorbital nerve ,Transient Receptor Potential Channels ,0302 clinical medicine ,Oximes ,trigeminal neuropathic pain ,4-hydroxynonenal ,CCL2 ,CION ,hydrogen peroxide ,NADPH oxidase ,medicine ,Animals ,TRPA1 Cation Channel ,Chemokine CCL2 ,Mice, Knockout ,Thioctic Acid ,Chemistry ,Macrophages ,Monocyte ,Acetophenones ,Nerve injury ,Oxidative Stress ,030104 developmental biology ,Nociception ,Allodynia ,medicine.anatomical_structure ,Hyperalgesia ,Purines ,Anesthesia ,Neuropathic pain ,Neuralgia ,Acetanilides ,Neurology (clinical) ,Sciatic nerve ,Clodronic Acid ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Despite intense investigation, the mechanisms of the different forms of trigeminal neuropathic pain remain substantially unidentified. The transient receptor potential ankyrin 1 channel (encoded by TRPA1 ) has been reported to contribute to allodynia or hyperalgesia in some neuropathic pain models, including those produced by sciatic nerve constriction. However, the role of TRPA1 and the processes that cause trigeminal pain-like behaviours from nerve insult are poorly understood. The role of TRPA1, monocytes and macrophages, and oxidative stress in pain-like behaviour evoked by the constriction of the infraorbital nerve in mice were explored. C57BL/6 and wild-type ( Trpa1+/+ ) mice that underwent constriction of the infraorbital nerve exhibited prolonged (20 days) non-evoked nociceptive behaviour and mechanical, cold and chemical hypersensitivity in comparison to sham-operated mice ( P < 0.05– P < 0.001). Both genetic deletion of Trpa1 ( Trpa1−/− ) and pharmacological blockade (HC-030031 and A-967079) abrogated pain-like behaviours (both P < 0.001), which were abated by the antioxidant, α-lipoic acid, and the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin (both P < 0.001). Nociception and hypersensitivity evoked by constriction of the infraorbital nerve was associated with intra- and perineural monocytic and macrophagic invasion and increased levels of oxidative stress by-products (hydrogen peroxide and 4-hydroxynonenal). Attenuation of monocyte/macrophage increase by systemic treatment with an antibody against the monocyte chemoattractant chemokine (C-C motif) ligand 2 (CCL2) or the macrophage-depleting agent, clodronate (both P < 0.05), was associated with reduced hydrogen peroxide and 4-hydroxynonenal perineural levels and pain-like behaviours (all P < 0.01), which were abated by perineural administration of HC-030031, α-lipoic acid or the anti-CCL2 antibody (all P < 0.001). The present findings propose that, in the constriction of the infraorbital nerve model of trigeminal neuropathic pain, pain-like behaviours are entirely mediated by the TRPA1 channel, targeted by increased oxidative stress by-products released from monocytes and macrophages clumping at the site of nerve injury. * Abbreviations : 4-HNE = : 4-hydroxynonenal AITC = : allyl isothiocyanate A-967079 = : (1 E ,3 E )-1-(4-Fluorophenyl)-2-methyl-1-penten-3-one oxime CION = : constriction of the infraorbital nerve HC-030031 = : (2-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)- N -(4-isopropylphenyl) acetamide) LCL = : liposome-encapsulated clodronate
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- 2016
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14. TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice
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Muryel De Carvalho Goncalves, Pierangelo Geppetti, Simone Li Puma, Francesco De Logu, Serena Materazzi, Silvia Benemei, Juliano Ferreira, Piyush Jain, Romina Nassini, Ilaria M. Marone, and Nigel W. Bunnett
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Male ,0301 basic medicine ,Vascular smooth muscle ,Sensory Receptor Cells ,Migraine Disorders ,Pain ,Stimulation ,Vasodilation ,Pharmacology ,Nitric oxide ,Mice ,Nitroglycerin ,03 medical and health sciences ,Trigeminal ganglion ,Transient receptor potential channel ,chemistry.chemical_compound ,Transient Receptor Potential Channels ,0302 clinical medicine ,medicine ,oxidative stress ,Animals ,migraine ,TRPA1 Cation Channel ,Mice, Knockout ,Chemistry ,Aldehyde Dehydrogenase, Mitochondrial ,Headache ,ion channels ,Migraine, glyceryl trinitrate, TRPA1 ,Original Articles ,trigeminal headache: experimental models ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,Allodynia ,Trigeminal Ganglion ,Hyperalgesia ,Cell Body ,NADPH Oxidase 1 ,Nociceptor ,Neurology (clinical) ,medicine.symptom ,030217 neurology & neurosurgery ,psychological phenomena and processes - Abstract
Glyceryl trinitrate administration causes prolonged mechanical allodynia in rodents, which correlates temporally with delayed migraine attacks in patients. Marone et al. show that the allodynia is mediated by TRPA1 activation in cell bodies of trigeminal neurons and ensuing oxidative stress. This neuronal pathway may be of relevance to migraine-like headaches., Glyceryl trinitrate is administered as a provocative test for migraine pain. Glyceryl trinitrate causes prolonged mechanical allodynia in rodents, which temporally correlates with delayed glyceryl trinitrate-evoked migraine attacks in patients. However, the underlying mechanism of the allodynia evoked by glyceryl trinitrate is unknown. The proalgesic transient receptor potential ankyrin 1 (TRPA1) channel, expressed by trigeminal nociceptors, is sensitive to oxidative stress and is targeted by nitric oxide or its by-products. Herein, we explored the role of TRPA1 in glyceryl trinitrate-evoked allodynia. Systemic administration of glyceryl trinitrate elicited in the mouse periorbital area an early and transient vasodilatation and a delayed and prolonged mechanical allodynia. The systemic, intrathecal or local administration of selective enzyme inhibitors revealed that nitric oxide, liberated from the parent drug by aldehyde dehydrogenase 2 (ALDH2), initiates but does not maintain allodynia. The central and the final phases of allodynia were respectively associated with generation of reactive oxygen and carbonyl species within the trigeminal ganglion. Allodynia was absent in TRPA1-deficient mice and was reversed by TRPA1 antagonists. Knockdown of neuronal TRPA1 by intrathecally administered antisense oligonucleotide and selective deletion of TRPA1 from sensory neurons in Advillin-Cre; Trpa1fl/fl mice revealed that nitric oxide-dependent oxidative and carbonylic stress generation is due to TRPA1 stimulation, and resultant NADPH oxidase 1 (NOX1) and NOX2 activation in the soma of trigeminal ganglion neurons. Early periorbital vasodilatation evoked by glyceryl trinitrate was attenuated by ALDH2 inhibition but was unaffected by TRPA1 blockade. Antagonists of the calcitonin gene-related peptide receptor did not affect the vasodilatation but partially inhibited allodynia. Thus, although both periorbital allodynia and vasodilatation evoked by glyceryl trinitrate are initiated by nitric oxide, they are temporally and mechanistically distinct. While vasodilatation is due to a direct nitric oxide action in the vascular smooth muscle, allodynia is a neuronal phenomenon mediated by TRPA1 activation and ensuing oxidative stress. The autocrine pathway, sustained by TRPA1 and NOX1/2 within neuronal cell bodies of trigeminal ganglia, may sensitize meningeal nociceptors and second order trigeminal neurons to elicit periorbital allodynia, and could be of relevance for migraine-like headaches evoked by glyceryl trinitrate in humans.
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- 2018
15. The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives
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Raquel Tonello, Francesco De Logu, Serena Materazzi, Elisabetta Coppi, Pierangelo Geppetti, Ilaria M. Marone, Delia Preti, Silvia Benemei, Alberto Chiarugi, Riccardo Patacchini, Tiziano Tuccinardi, Camilla Fusi, and Romina Nassini
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Pharmacology ,Voltage-dependent calcium channel ,Chemistry ,Analgesic ,food and beverages ,Transient receptor potential channel ,Nociception ,TRPA1 Cation Channel ,Hyperalgesia ,medicine ,Nociceptor ,medicine.symptom ,Propyphenazone ,medicine.drug - Abstract
Background and Purpose Although still used by hundreds of millions of people worldwide, the mechanism of the analgesic action of the pyrazolone derivatives (PDs), dipyrone, propyphenazone and antipyrine remains unknown. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed by nociceptors, is emerging as a major pain transduction pathway. We hypothesized that PDs target the TRPA1 channel and by this mechanism produce their analgesic effect.
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- 2015
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16. The blockade of transient receptor potential ankirin 1 (TRPA1) signalling mediates antidepressant- and anxiolytic-like actions in mice
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Serena Materazzi, Bruno Lobão Soares, Elaine C. Gavioli, Daiana Minocci, Ilaria M. Marone, Juliana Cavalcante de Moura, Vanessa de Paula Soares Rachetti, Romina Nassini, Maíra Macedo Noroes, Pierangelo Geppetti, Eunice André, and Delia Preti
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Pharmacology ,Agonist ,Elevated plus maze ,medicine.drug_class ,TRPV1 ,Antagonist ,food and beverages ,Anxiolytic ,medicine ,Antidepressant ,Anxiety ,medicine.symptom ,Psychology ,psychological phenomena and processes ,Behavioural despair test - Abstract
Background and Purpose Transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) are involved in many biological processes, including nociception and hyperalgesia. Whereas the involvement of TRPV1 in psychiatric disorders such as anxiety and depression has been reported, little is known regarding the role of TRPA1 in these conditions. Experimental Approach We investigated the role of TRPA1 in mice models of depression [forced swimming test (FST)] and anxiety [elevated plus maze (EPM) test]. Key Results Administration of the TRPA1 antagonist (HC030031, 30 nmol in 2 μL, i.c.v.) reduced immobility time in the FST. Similar results were obtained after oral administration of HC030031 (30–300 mg·kg−1). The reduction in immobility time in FST induced by HC030031 (100 mg·kg−1) was completely prevented by pretreatment with TRPA1 agonist, cinnamaldehyde (50 mg·kg−1, p.o.), which per se was inactive. In the EPM test, pretreatment with cinnamaldehyde (50 mg·kg−1, p.o.), which per se did not affect behaviour response, prevented the anxiolytic-like effect (increased open arm exploration) evoked by TRPA1 blockade (HC030031, 100 mg·kg−1, p.o.). Treatment with either cinnamaldehyde or HC030031 did not affect spontaneous ambulation. Furthermore, TRPA1-deficient mice showed anxiolytic- and antidepressant-like phenotypes in the FST and EPM test respectively. Conclusion and Implications The present findings indicate that genetic deletion or pharmacological blockade of TRPA1 produces inhibitory activity in mouse models of anxiety and depression. These results imply that TRPA1 exerts tonic control, promoting anxiety and depression, and that TRPA1 antagonism has potential as an innovative strategy for the treatment of anxiety and mood disorders.
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- 2014
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17. JAK2V617F Variant Allele Frequency Identifies Patients with Polycythemia Vera (PV) at High Risk for Venous Thrombosis
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Giacomo Coltro, Tiziano Barbui, Ilaria M. Marone, Carmela Mannarelli, Giuseppe Gaetano Loscocco, Chiara Paoli, Alessandro Pancrazzi, Benedetta Sordi, Alessandro M. Vannucchi, Francesco Mannelli, Paola Guglielmelli, and Francesca Gesullo
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,Cell Biology ,Hematology ,Hematocrit ,medicine.disease ,Biochemistry ,Gastroenterology ,Thrombosis ,Log-rank test ,Venous thrombosis ,Polycythemia vera ,Diabetes mellitus ,Internal medicine ,medicine ,Leukocytosis ,Risk factor ,medicine.symptom ,business - Abstract
Background. Cardiovascular (CV) events are leading cause of morbidity and mortality in PV. Current risk stratification is based on variables predicting thrombotic risk, ie age >60y and history of thrombosis. Recent studies focused on additional thrombotic risk factors in PV, including generic CV factors and leukocytosis. PV patients (pts) are JAK2V617F mutated, and present wide heterogeneity in variant allele frequency (VAF); it was shown that a VAF >75% was associated with higher number of thrombotic events after diagnosis (Vannucchi AM, Leukemia 2007), but the prognostic role of JAK2 VAF is still debated. Aim. The aim of the study was to evaluate the impact of JAK2V617F VAF on rate of thrombosis in WHO-2016 defined PV pts. Patients and Method. In the CRIMM (Florence) database, a total of 577 pts with a JAK2VF VAF determined within 3 years from diagnosis, who met the 2016 WHO criteria for PV, were identified. All pts had information regarding thromboembolic events, including history of thrombosis, occurrence, type and date of thrombosis in the follow-up (FU) and presence of CV risk factors (smoking, hypertension, and diabetes mellitus). Thrombosis‐free survival (TFS) was determined from the time of diagnosis to the time the first thrombotic event occurred. Pts in whom thrombosis did not occur were censored at the time of last FU. Pre-receiver operating characteristic (ROC) plots were used to determine cutoff levels for continuous variables of interest. Differences in the distribution of continuous variables between categories were analyzed by Mann-Whitney or Kruskal-Wallis test. Pts' groups with nominal variables were compared by χ2 test. TFS was estimated by Kaplan Meier analysis; log rank test was used to compare TFS difference between groups. Cox proportional hazards regression was used for multivariable analysis. A two tailed P ≤ 0.05 was considered statistically significant. Results. The median age of pts at diagnosis was 61y, 308 (53.4%) were above 60y; 57.2% were males. All pts were mutated for JAK2V617F with a median VAF 43% (range 1-100%), 62% had at least one CV risk factor; 83 (14.4%) pts suffered from an episode of thrombosis within 3 yr from, or coincident with, diagnosis. The median FU was 7.3y (0.6-35.9y) during which 87 pts (15.1%) developed thrombosis. (50 arterial and 45 venous thrombosis). During the FU, 110 pts (19.1%) died. A JAK2VAF of ≥60% cutoff level, as determined by ROC analysis, correlated with measurements of stimulated erythropoiesis (higher hematocrit, lower mean cell volume and serum ferritin; all P60% had greater risk to progress to PPV-MF (RR 8.5, P Conclusions. This study indicates that conventionally-defined high-risk PV pts with a JAK2V617F VAF ≥60% suffer from increased rate of venous events and might be worthwhile of more intensive antithrombotic prophylaxis. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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- 2018
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18. Glutathione, glutathione disulfide, and S-glutathionylated proteins in cell cultures
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Alberto Farolfi, Ilaria M. Marone, Ranieri Rossi, Aldo Milzani, Isabella Dalle-Donne, Michele Zanoni, Romina Nassini, Federico Galvagni, Anna Tesei, Sara Pignatta, and Daniela Giustarini
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Glutathione, Glutathione disulfide, S-glutathionylated proteins, Cell cultures ,medicine.disease_cause ,Biochemistry ,chemistry.chemical_compound ,Physiology (medical) ,Neoplasms ,medicine ,Animals ,Humans ,S-glutathionylated proteins ,Aorta ,Cells, Cultured ,chemistry.chemical_classification ,Glutathione Disulfide ,Chemistry ,Proteins ,Glutathione ,Cell cultures ,Redox status ,Oxidative Stress ,Cell culture ,Ethylmaleimide ,Disulfiram ,Glutathione disulfide ,Thiol ,Cattle ,Endothelium, Vascular ,Oxidation-Reduction ,Protein Processing, Post-Translational ,Oxidative stress ,DNA ,medicine.drug - Abstract
The analysis of the global thiol-disulfide redox status in tissues and cells is a challenging task since thiols and disulfides can undergo artificial oxido-reductions during sample manipulation. Because of this, the measured values, in particular for disulfides, can have a significant bias. Whereas this methodological problem has already been addressed in samples of red blood cells and solid tissues, a reliable method to measure thiols and disulfides in cell cultures has not been previously reported. Here, we demonstrate that the major artifact occurring during thiol and disulfide analysis in cultured cells is represented by glutathione disulfide (GSSG) and S-glutathionylated proteins (PSSG) overestimation, due to artificial oxidation of glutathione (GSH) during sample manipulation, and that this methodological problem can be solved by the addition of N-ethylmaleimide (NEM) immediately after culture medium removal. Basal levels of GSSG and PSSG in different lines of cultured cells were 3-5 and 10-20 folds higher, respectively, when the cells were processed without NEM. NEM pre-treatment also prevented the artificial reduction of disulfides that occurs during the pre-analytical phase when cells are exposed to an oxidant stimulus. In fact, in the absence of NEM, after medium removal, GSH, GSSG and PSSG levels restored their initial values within 15-30 min, due to the activity of reductases and the lack of the oxidant. The newly developed protocol was used to measure the thiol-disulfide redox status in 16 different line cells routinely used for biomedical research both under basal conditions and after treatment with disulfiram, a thiol-specific oxidant (0-200 μM concentration range). Our data indicate that, in most cell lines, treatment with disulfiram affected the levels of GSH and GSSG only at the highest concentration. On the other hand, PSSG levels increased significantly also at the lower concentrations of the drug, and the rise was remarkable (from 100 to 1000 folds at 200 μM concentration) and dose-dependent for almost all the cell lines. These data support the suitability of the analysis of PSSG in cultured cells as a biomarker of oxidative stress.
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- 2015
19. Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1
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Camilla Fusi, Daiana Minocci, Tiziano Tuccinardi, Romina Nassini, Mariarosaria Di Tommaso, Tommaso Susini, Silvia Benemei, Giuseppe Pieraccini, Elisabetta Coppi, Gloriano Moneti, Ilaria M. Marone, Pierangelo Geppetti, Francesco De Logu, Gabriela Trevisan, and Serena Materazzi
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Male ,Patch-Clamp Techniques ,General Physics and Astronomy ,Pharmacology ,aromatase inhibitors ,Rats, Sprague-Dawley ,Mice ,chemistry.chemical_compound ,Transient Receptor Potential Channels ,Exemestane ,Aromatase ,TRPA1 Cation Channel ,Neurogenic inflammation ,Multidisciplinary ,Behavior, Animal ,biology ,Letrozole ,food and beverages ,Nociception ,Nociceptor ,Steroids ,medicine.symptom ,psychological phenomena and processes ,medicine.drug ,medicine.medical_specialty ,TRPA1 ,Pain ,Nerve Tissue Proteins ,Inflammation ,Anastrozole ,Article ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Internal medicine ,Nitriles ,medicine ,Animals ,Humans ,Cysteine ,TRPC Cation Channels ,business.industry ,Neuropeptides ,General Chemistry ,Triazoles ,Rats ,Androstadienes ,Mice, Inbred C57BL ,HEK293 Cells ,Endocrinology ,chemistry ,biology.protein ,Calcium ,Calcium Channels ,business - Abstract
Use of aromatase inhibitors (AIs), exemestane, letrozole and anastrozole, for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. The electrophilic nature of AIs suggests that they may target the transient receptor potential ankyrin 1 (TRPA1) channel, a major pathway in pain transmission and neurogenic inflammation. AIs evoke TRPA1-mediated calcium response and current in rodent nociceptors and human cells expressing the recombinant channel. In mice, AIs produce acute nociception, which is exaggerated by pre-exposure to proalgesic stimuli, and, by releasing sensory neuropeptides, neurogenic inflammation in peripheral tissues. AIs also evoke mechanical allodynia and decreased grip strength, which do not undergo desensitization on prolonged AI administration. These effects are markedly attenuated by TRPA1 pharmacological blockade or in TRPA1-deficient mice. TRPA1 is a major mediator of the proinflammatory/proalgesic actions of AIs, thus suggesting TRPA1 antagonists for the treatment of pain symptoms associated with AI use., Use of aromatase inhibitors for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. Here the authors show that in mice, TRPA1 is a major mediator of the proinflammatory and proalgesic actions of aromatase inhibitors.
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- 2014
20. Exendin-4 Induces Cell Adhesion and Differentiation and Counteracts the Invasive Potential of Human Neuroblastoma Cells
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Corinna Giuliani, Cristiana Deledda, Roberta Squecco, Alessandro Peri, Ilaria Cellai, Fabio Francini, Benedetta Fibbi, Ilaria M. Marone, Susanna Benvenuti, Giulia Modi, Paola Luciani, and Gabriella B. Vannelli
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Anatomy and Physiology ,L1 ,Cellular differentiation ,Cell Culture Techniques ,lcsh:Medicine ,Gene Expression ,Membrane Potentials ,Extracellular matrix ,Neuroblastoma ,Cell Movement ,Molecular Cell Biology ,Receptors, Glucagon ,lcsh:Science ,Neurological Tumors ,Cells, Cultured ,Multidisciplinary ,Reverse Transcriptase Polymerase Chain Reaction ,Cell adhesion molecule ,digestive, oral, and skin physiology ,Cell Differentiation ,Cell migration ,Extracellular Matrix ,Cell biology ,Electrophysiology ,Oncology ,Medicine ,Microtubule-Associated Proteins ,Protein Binding ,Research Article ,Cell Physiology ,endocrine system ,Cell Survival ,Synaptophysin ,Neurophysiology ,tau Proteins ,Biology ,Glucagon-Like Peptide-1 Receptor ,Receptors, Urokinase Plasminogen Activator ,Cell Line, Tumor ,Cell Adhesion ,Humans ,Hypoglycemic Agents ,Neoplasm Invasiveness ,Vitronectin ,Cell adhesion ,Venoms ,lcsh:R ,Soluble cell adhesion molecules ,Cancers and Neoplasms ,Cellular Neuroscience ,Exenatide ,lcsh:Q ,Neural cell adhesion molecule ,Calcium Channels ,exendin-4 ,neuroblastoma ,tumor ,Molecular Neuroscience ,Peptides ,Neuroscience - Abstract
Exendin-4 is a molecule currently used, in its synthetic form exenatide, for the treatment of type 2 diabetes mellitus. Exendin-4 binds and activates the Glucagon-Like Peptide-1 Receptor (GLP-1R), thus inducing insulin release. More recently, additional biological properties have been associated to molecules that belong to the GLP-1 family. For instance, Peptide YY and Vasoactive Intestinal Peptide have been found to affect cell adhesion and migration and our previous data have shown a considerable actin cytoskeleton rearrangement after exendin-4 treatment. However, no data are currently available on the effects of exendin-4 on tumor cell motility. The aim of this study was to investigate the effects of this molecule on cell adhesion, differentiation and migration in two neuroblastoma cell lines, SH-SY5Y and SK-N-AS. We first demonstrated, by Extra Cellular Matrix cell adhesion arrays, that exendin-4 increased cell adhesion, in particular on a vitronectin substrate. Subsequently, we found that this molecule induced a more differentiated phenotype, as assessed by i) the evaluation of neurite-like protrusions in 3D cell cultures, ii) the analysis of the expression of neuronal markers and iii) electrophysiological studies. Furthermore, we demonstrated that exendin-4 reduced cell migration and counteracted anchorage-independent growth in neuroblastoma cells. Overall, these data indicate for the first time that exendin-4 may have anti-tumoral properties.
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- 2013
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