46 results on '"Rufini, S."'
Search Results
2. Evidence of domain formation in cardiolipin-glycerophospholipid mixed monolayers: A thermodynamic and AFM study
- Author
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Sennato, S., Rufini, S., Bordi, F., Cametti, C., Coluzza, C., and Desideri, A.
- Subjects
Cardiolipin -- Thermal properties ,Cardiolipin -- Chemical properties ,Choline -- Thermal properties ,Choline -- Chemical properties ,Thermodynamics -- Research ,Atomic force microscopy -- Usage ,Chemicals, plastics and rubber industries - Abstract
The thermodynamic behavior of mixed monolayers of cardiolipin-dipalmitoylphosphatidylcholine (CLP-DPPC) and cardiolipin-dipalmitoylphosphatidylethanolamine (CLP-DPPE) is investigated by studying their Langmuir surface pressure and surface potential isotherms at different cardiolipin molar fractions. The overall thermodynamic behavior is independent of mole fraction for the mixed CLP-DPPC monolayers while a critical fraction exists for the CLP-DPPE monolayers.
- Published
- 2005
3. Cratoxylum formosum ssp. pruniflorum activates the TRAIL death receptor complex and inhibits topoisomerase I
- Author
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Nonpunya, A., primary, Sethabouppha, B., additional, Rufini, S., additional, and Weerapreeyakul, N., additional
- Published
- 2018
- Full Text
- View/download PDF
4. Sticholysin II Identifies Intracellular Lipid Deposits in Niemann Pick C Fibroblasts
- Author
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Chieppa, G, Zaratti, A, Taurisano, R, Deodato, F, Carrozzo, R, Piemonte, F, D'Arcangelo, G, Frank, C, Dionisi Vici, C, and Rufini, S
- Subjects
Sphingomyelin ,Cholera toxin filipin ,Confocal microscopy ,Sticholysin II ,Cholesterol ,Niemann Pick C disease ,Human fibroblasts ,Lysosomal diseases ,Settore BIO/09 - Published
- 2016
5. Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis
- Author
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Ciccacci, C, primary, Conigliaro, P, additional, Perricone, C, additional, Rufini, S, additional, Triggianese, P, additional, Politi, C, additional, Novelli, G, additional, Perricone, R, additional, and Borgiani, P, additional
- Published
- 2016
- Full Text
- View/download PDF
6. Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease
- Author
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D’Arcangelo, G., primary, Grossi, D., additional, Racaniello, M., additional, Cardinale, A., additional, Zaratti, A., additional, Rufini, S., additional, Cutarelli, A., additional, Tancredi, V., additional, Merlo, D., additional, and Frank, C., additional
- Published
- 2016
- Full Text
- View/download PDF
7. PLA2 stimulation of Na/H antiport and proliferation in rat aortic smooth muscle cells
- Author
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RUFINI S, DE VITO P, BALESTRO N, PESCATORI N, LULY P, INCERPI, Sandra, Rufini, S, DE VITO, P, Balestro, N, Pescatori, N, Luly, P, and Incerpi, Sandra
- Subjects
Settore BIO/09 - Published
- 1999
8. A novel pharmacological approach and identification of peripheral cellular biomarkers in Niemann-Pick Type C disease patients
- Author
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Frank, C., Rufini, S., Grossi, D., De Chiara, G., Dionisi Vici, C., Biagini, Giuseppe, Tancredi, V., Merlo, D., and D’Arcangelo, G.
- Subjects
Biomarkers ,Niemann-Pick Type C Disease - Published
- 2010
9. Skeletal muscle differentiation and Rho GTPases: bacterial toxins as tools to control degeneration
- Author
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Travaglione, Sara, Falzano, L., Messina, Graziella, Fabbri, A., Grossi, Milena, Rufini, S., and Fiorentini, C.
- Published
- 2004
10. Monoclonal antibody fragment from combinatorial phage display library neutralizes alpha-latrotoxin activity and abolishes black widow spider venom lethality, in mice
- Author
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Bugli, Francesca, Graffeo, Rosalia, Paroni Sterbini, Francesco, Torelli, Riccardo, Masucci, Luca, Sali, Michela, Grasso, A, Rufini, S, Ricci, Enzo, Fadda, Giovanni, Pescatori, M, Bugli, Francesca (ORCID:0000-0001-9038-3233), Masucci, Luca (ORCID:0000-0002-8358-6726), Sali, Michela (ORCID:0000-0003-3609-2990), Ricci, Enzo (ORCID:0000-0003-3092-3597), Bugli, Francesca, Graffeo, Rosalia, Paroni Sterbini, Francesco, Torelli, Riccardo, Masucci, Luca, Sali, Michela, Grasso, A, Rufini, S, Ricci, Enzo, Fadda, Giovanni, Pescatori, M, Bugli, Francesca (ORCID:0000-0001-9038-3233), Masucci, Luca (ORCID:0000-0002-8358-6726), Sali, Michela (ORCID:0000-0003-3609-2990), and Ricci, Enzo (ORCID:0000-0003-3092-3597)
- Abstract
Alpha-latrotoxin (alpha-ltx), a component of the venom of black widow spiders (BWSV), binds to higher vertebrates presynaptic nerve terminals, stimulating massive neurotransmitter release. This neurotoxic protein is responsible for most of the symptoms elicited in men by the bite of black widow spider (BWS), i.e. a neurological syndrome named latrodectism. By reasoning that targeting this single component would abrogate most of the effect of BWS envenomation, we took advantage of the antibody phage display technology to generate monoclonal Fab fragments able to bind and neutralize the alpha-ltx. To this aim, we immunized Balb/c mice with purified toxin and cloned their antibody repertoire in the pCombIII phage display vector. By combining a high-stringency affinity selection with a sensitive 45Ca(2+) uptake assay, we isolated a Fab fragment (FM1) able to bind the alpha-ltx in the low nM range and neutralize its ionophore activity, in vitro and in vivo. After the onset of overt symptomatology, administration of FM1 to experimentally envenomed mice induced remission of symptoms and prevented lethality. Since alpha-ltx is the only molecule responsible for the great toxicity of BWS bites in mammals, the FM1 Fab, highly effective in neutralizing the toxin in vivo, represents a promising immunotherapy reagent for treating latrodectic patients.
- Published
- 2008
11. Effects of chrysin on urinary testosterone levels in human males.
- Author
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Gambelunghe, C, Rossi, R, Sommavilla, M, Ferranti, C, Rossi, Riccardo, Ciculi, C, Gizzi, S, Micheletti, A, Rufini, S., Rossi, Riccardo (ORCID:0000-0001-7576-6316), Gambelunghe, C, Rossi, R, Sommavilla, M, Ferranti, C, Rossi, Riccardo, Ciculi, C, Gizzi, S, Micheletti, A, Rufini, S., and Rossi, Riccardo (ORCID:0000-0001-7576-6316)
- Abstract
The equilibrium of sexual hormones in both sexes is controlled in vertebrates by the enzyme aromatase, a member of the cytochrome P450 superfamily, which catalyzes the conversion of androstenedione and testosterone into estrone and estradiol, respectively. Flavonoids are diphenolic compounds present in whole grains, legumes, fruits, and vegetables that are strongly implicated as protective in coronary heart disease, stroke, and cancer. One flavonoid, chrysin, found in high concentrations in honey and propolis, has been shown to be an inhibitor of aromatase enzyme activity. These foods are often used as supplements, particulary by sportsmen for their energetic and antioxidant properties. The aim of this study was to verify if daily treatment for 21 days with propolis and honey, containing chrysin, would modify urinary concentrations of testosterone in volunteer male subjects. In fact, aromatase inhibition by chrysin could block the conversion of androgens into estrogens with a consequent increase of testosterone, eventually measurable in urine samples. The obtained data did not show alterations of the levels of testosterone in the volunteers after 7, 14, and 21 days of treatment in comparison with baseline values and compared with measurements on the control subjects at the same time. In conclusion, the use of these foods for 21 days at the doses usually taken as oral supplementation does not have effects on the equilibrium of testosterone in human males.
- Published
- 2003
12. Evidence of Domain Formation in Cardiolipin−Glycerophospholipid Mixed Monolayers. A Thermodynamic and AFM Study
- Author
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Sennato, S., primary, Bordi, F., additional, Cametti, C., additional, Coluzza, C., additional, Desideri, A., additional, and Rufini, S., additional
- Published
- 2005
- Full Text
- View/download PDF
13. Enhanced secretion of heterologous proteins in by overexpression of the GDP-mannose pyrophosphorylase, KlPsa1p
- Author
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UCCELLETTI, D, primary, STANEVA, D, additional, RUFINI, S, additional, VENKOV, P, additional, and PALLESCHI, C, additional
- Published
- 2005
- Full Text
- View/download PDF
14. Cytotoxic necrotizing factor 1 hinders skeletal muscle differentiation in vitro by perturbing the activation/deactivation balance of Rho GTPases
- Author
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Travaglione, S, primary, Messina, G, additional, Fabbri, A, additional, Falzano, L, additional, Giammarioli, A M, additional, Grossi, M, additional, Rufini, S, additional, and Fiorentini, C, additional
- Published
- 2004
- Full Text
- View/download PDF
15. PLA2stimulation of Na+/H+antiport and proliferation in rat aortic smooth muscle cells
- Author
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Rufini, S., primary, De Vito, P., additional, Balestro, N., additional, Pescatori, M., additional, Luly, P., additional, and Incerpi, S., additional
- Published
- 1999
- Full Text
- View/download PDF
16. Hyperhomocyatcinemia is an independent risk factor for carotid atherosclerosis
- Author
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Lupatelli, G., primary, Rufini, S., additional, Lombardini, R., additional, Siepi, D., additional, Locatt, E.H., additional, and Mannarino, E., additional
- Published
- 1998
- Full Text
- View/download PDF
17. Cytotoxic necrotizing factor 1 hinders skeletal muscle differentiation in vitro by perturbing the activation/deactivation balance of Rho GTPases.
- Author
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Travaglione, S., Messina, G., Fabbri, A., Falzano, L., Giammarioli, A. M., Grossi, M., Rufini, S., and Fiorentini, C.
- Subjects
MORPHOGENESIS ,MYOBLASTS ,CYTOSKELETAL proteins ,CELL death ,RHO GTPases ,MUSCLES - Abstract
The current knowledge assigns a crucial role to the Rho GTPases family (Rho, Rac, Cdc42) in the complex transductive pathway leading to skeletal muscle cell differentiation. Their exact function in myogenesis, however, remains largely undefined. The protein toxin CNF1 was herein employed as a tool to activate Rho, Rac and Cdc42 in the myogenic cell line C2C12. We demonstrated that CNF1 impaired myogenesis by affecting the muscle regulatory factors MyoD and myogenin and the structural protein MHC expressions. This was principally driven by Rac/Cdc42 activation whereas Rho apparently controlled only the fusion process. More importantly, we proved that a controlled balance between Rho and Rac/Cdc42 activation/deactivation state was crucial for the correct execution of the differentiation program, thus providing a novel view for the role of Rho GTPases in muscle cell differentiation. Also, the use of Rho hijacking toxins can represent a new strategy to pharmacologically influence the differentiative process.Cell Death and Differentiation (2005) 12, 78-86. doi:10.1038/sj.cdd.4401522 Published online 29 October 2004 [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
18. Effects of chrysin on urinary testosterone levels in human males.
- Author
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Gambelunghe C, Rossi R, Sommavilla M, Ferranti C, Ciculi C, Gizzi S, Micheletti A, and Rufini S
- Published
- 2003
19. PLA2 stimulation of Na+/H+ antiport and proliferation in rat aortic smooth muscle cells.
- Author
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Rufini, S. and De Vito, P.
- Subjects
- *
PHOSPHOLIPASE A2 , *SODIUM cotransport systems , *AORTA , *MUSCLE cells , *RAT physiology , *CYTOLOGY , *PHYSIOLOGY - Abstract
Studies the influence of phospholipase A2 (PLA2) on sodium/hydrogen antiport and proliferation in rat aortic smooth muscle cells (RASMC). Effects of ammodytin L (AMDL) and pancreatic secretory PLA2 on [3H]thymidine incorporation in RASMC; Role of growth factors in the mitogenic response of RASMC to PLA2 or AMDL stimulation.
- Published
- 1999
- Full Text
- View/download PDF
20. Passionflower fruit -- a 'new' source of lycopene?
- Author
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Mourvaki E, Stefani G, Rossi R, and Rufini S
- Published
- 2005
21. Concanavalin a blocks black widow spider toxin stimulation of transmitter release from synaptosomes
- Author
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Grasso, A., Rufini, S., and Senni, I.
- Published
- 1978
- Full Text
- View/download PDF
22. Black widow spider toxin-induced calcium fluxes and transmitter release in a neurosecretory cell line
- Author
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Grasso, A., primary, Alemà, S., additional, Rufini, S., additional, and Senni, M. I., additional
- Published
- 1980
- Full Text
- View/download PDF
23. Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts
- Author
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Antonella Canini, Stefano Rufini, Carla Montesano, Mattia Falconi, Daniele Lettieri-Barbato, Antonia Marcone, Raffaella Faraonio, Susanna De Stefano, Noemi Poerio, Flavia Tortolici, Maurizio Mattei, Antonella Minutolo, Roberta Bernardini, Simona Sennato, Federico Iacovelli, Giuseppina Minopoli, Stefano Casciardi, Gabriele Di Marco, Katia Aquilano, Maurizio Fraziano, Veronica Ceci, Marina Potestà, Angelo Gismondi, Aquilano, K., Ceci, V., Gismondi, A., De Stefano, S., Iacovelli, F., Faraonio, R., Di Marco, G., Poerio, N., Minutolo, A., Minopoli, G., Marcone, A., Fraziano, M., Tortolici, F., Sennato, S., Casciardi, S., Potesta', GIAN LUCA, Bernardini, R., Mattei, M., Falconi, M., Montesano, C., Rufini, S., Canini, A., and Lettieri-Barbato, D.
- Subjects
Small RNA ,Medicine (miscellaneous) ,Receptors, Tumor Necrosis Factor ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Gene Expression Regulation, Plant ,Adipocyte ,Adipocytes ,Insulin ,Nuts ,lcsh:QH301-705.5 ,0303 health sciences ,Molecular medicine ,food and beverages ,Cell biology ,Adipose Tissue ,RNA, Plant ,030220 oncology & carcinogenesis ,Cytokines ,Tumor necrosis factor alpha ,Female ,medicine.symptom ,Signal transduction ,General Agricultural and Biological Sciences ,Disease model ,Metabolism ,Inflammation ,Biology ,Settore BIO/09 ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,3T3-L1 Cells ,microRNA ,medicine ,Animals ,Humans ,RNA, Messenger ,Settore BIO/10 ,Desiccation ,030304 developmental biology ,Oligonucleotide ,Hypertrophy ,Mice, Inbred C57BL ,MicroRNAs ,Glucose ,HEK293 Cells ,RAW 264.7 Cells ,chemistry ,lcsh:Biology (General) ,Nanoparticles - Abstract
There is a growing interest in therapeutically targeting the inflammatory response that underlies age-related chronic diseases including obesity and type 2 diabetes. Through integrative small RNA sequencing, we show the presence of conserved plant miR159a and miR156c in dried nuts having high complementarity with the mammalian TNF receptor superfamily member 1a (Tnfrsf1a) transcript. We detected both miR159a and miR156c in exosome-like nut nanovesicles (NVs) and demonstrated that such NVs reduce Tnfrsf1a protein and dampen TNF-α signaling pathway in adipocytes. Synthetic single-stranded microRNAs (ss-miRs) modified with 2′-O-methyl group function as miR mimics. In plants, this modification naturally occurs on nearly all small RNAs. 2′-O-methylated ss-miR mimics for miR156c and miR159a decreased Tnfrsf1a protein and inflammatory markers in hypertrophic as well as TNF-α-treated adipocytes and macrophages. miR156c and miR159a mimics effectively suppress inflammation in mice, highlighting a potential role of plant miR-based, single-stranded oligonucleotides in treating inflammatory-associated metabolic diseases., Aquilano et al. identify conserved plant miR159a and miR156c in dried nuts and show that these miRNAs target TNF receptor superfamily member 1a to suppress TNF-α-mediated inflammation. This study highlights the potential of plant miR-based oligonucleotides as a therapeutic option to treat metabolic diseases hallmarked by inflammation.
- Published
- 2019
24. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue
- Author
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Massimo Federici, Roberta Bernardini, Federico Iacovelli, Stefano Rufini, Riccardo Turchi, Maria Zingariello, Raffaella Faraonio, Mattia Falconi, Lorenzo De Angelis, Katia Aquilano, Fiorella Piemonte, Giulio Guidobaldi, Piergiorgio La Rosa, Daniele Lettieri-Barbato, Simone Carotti, Maria Francesconi, Maurizio Mattei, Sergio Morini, Flavia Tortolici, Viviana Casagrande, Turchi, R, Tortolici, F, Guidobaldi, G, Iacovelli, F, Falconi, M, Rufini, S, Faraonio, R, Casagrande, V, Federici, M, De Angelis, L, Carotti, S, Francesconi, M, Zingariello, M, Morini, S, Bernardini, R, Mattei, M, La Rosa, P, Piemonte, F, Lettieri-Barbato, D, and Aquilano, K.
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,diabetes mellitus, type 2 ,Friedreich ataxia ,insulin resistance ,Immunology ,Adipose tissue ,GPX4 ,Biochemistry ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Adipocyte ,Brown adipose tissue ,medicine ,lcsh:QH573-671 ,Settore BIO/10 ,biology ,lcsh:Cytology ,Lipid metabolism ,Cell Biology ,Biological sciences ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,type 2 ,Adipogenesis ,diabetes mellitus ,Frataxin ,biology.protein ,Thermogenesis ,030217 neurology & neurosurgery - Abstract
Decreased expression of mitochondrial frataxin (FXN) causes Friedreich’s ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
- Published
- 2020
25. Why Do the Cosmic Rays Induce Aging?
- Author
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Flavia Tortolici, Anna Giovanetti, Stefano Rufini, Giovanetti, A., Tortolici, F., and Rufini, S.
- Subjects
0301 basic medicine ,Senescence ,lcsh:QP1-981 ,Chemistry ,Physiology ,Sterile inflammation ,Mini Review ,aging ,Cosmic ray ,HZE ions ,Settore BIO/09 ,lcsh:Physiology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,cosmic rays ,030220 oncology & carcinogenesis ,Physiology (medical) ,Biophysics ,mitochondrion ,DNA damage ,cell signaling ,Living matter - Abstract
The increasing duration of space missions involves a progressively higher exposure of astronauts to cosmic rays, whose most hazardous component is made up of High-Atomic number and High-Energy (HZE) ions. HZE ions interact along their tracks with biological molecules inducing changes on living material qualitatively different from that observed after irradiation for therapeutic purposes or following nuclear accidents. HZE ions trigger in cells different responses initialized by DNA damage and mitochondria dysregulation, which cause a prolonged state of sterile inflammation in the tissues. These cellular phenomena may explain why spending time in space was found to cause the onset of a series of diseases normally related to aging. These changes that mimic aging but take place more quickly make space flights also an opportunity to study the mechanisms underlying aging. In this short review, we describe the biological mechanisms underlying cell senescence and aging; the peculiar characteristics of HZE ions, their interaction with living matter and the effects on the organism; the key role of mitochondria in HZE ion-induced health effects and aging-related phenomena.
- Published
- 2019
26. Effect of ammodytin L from Vipera ammodytes on L-6 cells from rat skeletal muscle
- Author
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P. De Vito, Stefano Rufini, Sandra Incerpi, Paolo Luly, Incerpi, Sandra, DE VITO, P., Luly, P., and Rufini, S.
- Subjects
Snake venom ,Time Factors ,Cytotoxicity ,chemistry.chemical_element ,Viper Venoms ,Calcium ,Settore BIO/09 ,Calcium in biology ,Cell Line ,Dose-Response Relationship ,chemistry.chemical_compound ,Phospholipase A2 ,Calcium influx ,medicine ,Animals ,Myocyte ,Creatine Kinase ,Egtazic Acid ,Molecular Biology ,Calcium metabolism ,Dose-Response Relationship, Drug ,biology ,Muscles ,Skeletal muscle ,Cell Differentiation ,Cell Biology ,L-6 cell ,Rats ,EGTA ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Myotoxin ,biology.protein ,Creatine kinase ,Drug - Abstract
Ammodytin L (AMDL) is a myotoxic phospholipase-like protein from the venom of Vipera ammodytes with a serine in position 49 instead of an aspartate, therefore this toxin is devoid of phospholipase activity, and the membrane-damaging effect does not involve any step of phospholipase activity. The aim of the present study was to analyze the effect of AMDL on L-6 cells from rat skeletal muscle to investigate its mechanism of action and the role of calcium ions in its muscle-damaging activity. Our data indicate that the effect of ammodytin L is strongly dependent on the degree of cell differentiation. Low doses of myotoxin gave rise to a marked release of creatine kinase in myotubes differentiated from L-6 myoblasts and the presence of calcium ions plays a role in the cytotoxic effect. The presence of EGTA in the incubation buffer reduced by 50% the release of creatine kinase. No membrane damage was observed in myoblasts, but there was a significant increase of intracellular calcium concentration measured with Fura-2. A non-specific membrane effect of AMDL was ruled out using platelets as reference cells: no platelet aggregation pattern and no increase in intracellular calcium were observed.
- Published
- 1995
27. Low Sulfur Amino Acid, High Polyunsaturated Fatty Acid Diet Inhibits Breast Cancer Growth.
- Author
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Turchi R, Tortolici F, Benvenuto M, Punziano C, De Luca A, Rufini S, Faraonio R, Bei R, Lettieri-Barbato D, and Aquilano K
- Subjects
- Animals, Mice, Cell Death, Fatty Acids pharmacology, Fatty Acids, Unsaturated pharmacology, Lipid Peroxidation, Lipid Peroxides, MCF-7 Cells, MDA-MB-231 Cells, Humans, Apoptosis, Breast Neoplasms pathology, Diet
- Abstract
Cancer cells may acquire resistance to stress signals and reprogram metabolism to meet the energetic demands to support their high proliferation rate and avoid death. Hence, targeting nutrient dependencies of cancer cells has been suggested as a promising anti-cancer strategy. We explored the possibility of killing breast cancer (BC) cells by modifying nutrient availability. We used in vitro models of BC (MCF7 and MDA-MB-231) that were maintained with a low amount of sulfur amino acids (SAAs) and a high amount of oxidizable polyunsatured fatty acids (PUFAs). Treatment with anti-apoptotic, anti-ferroptotic and antioxidant drugs were used to determine the modality of cell death. We reproduced these conditions in vivo by feeding BC-bearing mice with a diet poor in proteins and SAAs and rich in PUFAs (LSAA/HPUFA). Western blot analysis, qPCR and histological analyses were used to assess the anti-cancer effects and the molecular pathways involved. We found that BC cells underwent oxidative damage to DNA and proteins and both apoptosis and ferroptosis were induced. Along with caspases-mediated PARP1 cleavage, we found a lowering of the GSH-GPX4 system and an increase of lipid peroxides. A LSAA/HPUFA diet reduced tumor mass and its vascularization and immune cell infiltration, and induced apoptosis and ferroptotic hallmarks. Furthermore, mitochondrial mass was found to be increased, and the buffering of mitochondrial reactive oxygen species limited GPX4 reduction and DNA damage. Our results suggest that administration of custom diets, targeting the dependency of cancer cells on certain nutrients, can represent a promising complementary option for anti-cancer therapy.
- Published
- 2022
- Full Text
- View/download PDF
28. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
- Author
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Rosina M, Ceci V, Turchi R, Chuan L, Borcherding N, Sciarretta F, Sánchez-Díaz M, Tortolici F, Karlinsey K, Chiurchiù V, Fuoco C, Giwa R, Field RL, Audano M, Arena S, Palma A, Riccio F, Shamsi F, Renzone G, Verri M, Crescenzi A, Rizza S, Faienza F, Filomeni G, Kooijman S, Rufini S, de Vries AAF, Scaloni A, Mitro N, Tseng YH, Hidalgo A, Zhou B, Brestoff JR, Aquilano K, and Lettieri-Barbato D
- Subjects
- Adipocytes, Brown metabolism, Macrophages metabolism, Mitochondria metabolism, Uncoupling Protein 1 metabolism, Adipose Tissue, Brown metabolism, Thermogenesis physiology
- Abstract
Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT., Competing Interests: Declaration of interests J.R.B. has a pending patent application related to mitochondria transfer. The other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
29. Ionizing Radiation-Induced Extracellular Vesicle Release Promotes AKT-Associated Survival Response in SH-SY5Y Neuroblastoma Cells.
- Author
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Tortolici F, Vumbaca S, Incocciati B, Dayal R, Aquilano K, Giovanetti A, and Rufini S
- Subjects
- Cell Line, Tumor, Cell Movement radiation effects, Cell Survival radiation effects, DNA Breaks radiation effects, DNA Repair radiation effects, Extracellular Vesicles radiation effects, Humans, Extracellular Vesicles metabolism, Neuroblastoma metabolism, Neuroblastoma pathology, Proto-Oncogene Proteins c-akt metabolism, Radiation, Ionizing
- Abstract
Radiation therapy is one of the most effective methods of tumor eradication; however, in some forms of neuroblastoma, radiation can increase the risk of secondary neoplasms, due to the ability of irradiated cells to transmit pro-survival signals to non-irradiated cells through vesicle secretion. The aims of this study were to characterize the vesicles released by the human neuroblastoma cell line SH-SY5Y following X-ray radiations and their ability to increase invasiveness in non-irradiated SH-SY5Y cells. We first purified the extracellular vesicles released by the SH-SY5Y cells following X-rays, and then determined their total amount, dimensions, membrane protein composition, and cellular uptake. We also examined the effects of these extracellular vesicles on viability, migration, and DNA damage in recipient SH-SY5Y cells. We found that exposure to X-rays increased the release of extracellular vesicles and altered their protein composition. These vesicles were readily uptaken by non-irradiated cells, inducing an increase in viability, migration, and radio-resistance. The same results were obtained in an MYCN -amplified SK-N-BE cell line. Our study demonstrates that vesicles released from irradiated neuroblastoma cells stimulate proliferation and invasiveness that correlate with the epithelial to mesenchymal transition in non-irradiated cells. Moreover, our results suggest that, at least in neuroblastomas, targeting the extracellular vesicles may represent a novel therapeutic approach to counteract the side effects associated with radiotherapy.
- Published
- 2021
- Full Text
- View/download PDF
30. Why Do the Cosmic Rays Induce Aging?
- Author
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Giovanetti A, Tortolici F, and Rufini S
- Abstract
The increasing duration of space missions involves a progressively higher exposure of astronauts to cosmic rays, whose most hazardous component is made up of High-Atomic number and High-Energy (HZE) ions. HZE ions interact along their tracks with biological molecules inducing changes on living material qualitatively different from that observed after irradiation for therapeutic purposes or following nuclear accidents. HZE ions trigger in cells different responses initialized by DNA damage and mitochondria dysregulation, which cause a prolonged state of sterile inflammation in the tissues. These cellular phenomena may explain why spending time in space was found to cause the onset of a series of diseases normally related to aging. These changes that mimic aging but take place more quickly make space flights also an opportunity to study the mechanisms underlying aging. In this short review, we describe the biological mechanisms underlying cell senescence and aging; the peculiar characteristics of HZE ions, their interaction with living matter and the effects on the organism; the key role of mitochondria in HZE ion-induced health effects and aging-related phenomena., (Copyright © 2020 Giovanetti, Tortolici and Rufini.)
- Published
- 2020
- Full Text
- View/download PDF
31. Correction: Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue.
- Author
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Turchi R, Tortolici F, Guidobaldi G, Iacovelli F, Falconi M, Rufini S, Faraonio R, Casagrande V, Federici M, De Angelis L, Carotti S, Francesconi M, Zingariello M, Morini S, Bernardini R, Mattei M, La Rosa P, Piemonte F, Lettieri-Barbato D, and Aquilano K
- Abstract
Since online publication of this article, the authors noticed that there was a basic citation error in PubMed citation data. Specifically, the name of the author "Piergiorgio La Rosa" is cited as "Rosa P" in the PubMed citation, when it should be "La Rosa P", "La Rosa" being the surname and "Piergiorgio" the name of the author.
- Published
- 2020
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32. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue.
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Turchi R, Tortolici F, Guidobaldi G, Iacovelli F, Falconi M, Rufini S, Faraonio R, Casagrande V, Federici M, De Angelis L, Carotti S, Francesconi M, Zingariello M, Morini S, Bernardini R, Mattei M, La Rosa P, Piemonte F, Lettieri-Barbato D, and Aquilano K
- Subjects
- Adipocytes metabolism, Adipose Tissue, Brown ultrastructure, Animals, Cold Temperature, Cyclic AMP-Dependent Protein Kinases metabolism, Diabetes Mellitus, Type 2 metabolism, Ferroptosis genetics, Friedreich Ataxia genetics, Hyperlipidemias genetics, Hyperlipidemias metabolism, Insulin Resistance genetics, Iron-Binding Proteins genetics, Leptin blood, Lipolysis genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Transmission, Mitochondria ultrastructure, Oxidative Stress genetics, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, RNA-Seq, Frataxin, Adipose Tissue, Brown metabolism, Friedreich Ataxia metabolism, Iron-Binding Proteins metabolism, Lipid Metabolism, Mitochondria metabolism, Thermogenesis genetics
- Abstract
Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
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- 2020
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33. Adipocyte metabolism is improved by TNF receptor-targeting small RNAs identified from dried nuts.
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Aquilano K, Ceci V, Gismondi A, De Stefano S, Iacovelli F, Faraonio R, Di Marco G, Poerio N, Minutolo A, Minopoli G, Marcone A, Fraziano M, Tortolici F, Sennato S, Casciardi S, Potestà M, Bernardini R, Mattei M, Falconi M, Montesano C, Rufini S, Canini A, and Lettieri-Barbato D
- Subjects
- 3T3-L1 Cells, Adipocytes drug effects, Adipose Tissue pathology, Animals, Cytokines metabolism, Female, Gene Expression Regulation, Plant drug effects, Glucose metabolism, HEK293 Cells, Humans, Hypertrophy, Inflammation genetics, Inflammation pathology, Insulin pharmacology, Mice, Mice, Inbred C57BL, MicroRNAs genetics, MicroRNAs metabolism, Nanoparticles chemistry, Nanoparticles ultrastructure, RAW 264.7 Cells, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Plant metabolism, Adipocytes metabolism, Desiccation, Nuts genetics, RNA, Plant genetics, Receptors, Tumor Necrosis Factor metabolism
- Abstract
There is a growing interest in therapeutically targeting the inflammatory response that underlies age-related chronic diseases including obesity and type 2 diabetes. Through integrative small RNA sequencing, we show the presence of conserved plant miR159a and miR156c in dried nuts having high complementarity with the mammalian TNF receptor superfamily member 1a (Tnfrsf1a) transcript. We detected both miR159a and miR156c in exosome-like nut nanovesicles (NVs) and demonstrated that such NVs reduce Tnfrsf1a protein and dampen TNF-α signaling pathway in adipocytes. Synthetic single-stranded microRNAs (ss-miRs) modified with 2'- O -methyl group function as miR mimics. In plants, this modification naturally occurs on nearly all small RNAs. 2'- O -methylated ss-miR mimics for miR156c and miR159a decreased Tnfrsf1a protein and inflammatory markers in hypertrophic as well as TNF-α-treated adipocytes and macrophages. miR156c and miR159a mimics effectively suppress inflammation in mice, highlighting a potential role of plant miR-based, single-stranded oligonucleotides in treating inflammatory-associated metabolic diseases., Competing Interests: Competing interestsThe authors declare no competing interests
- Published
- 2019
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34. Pharmacogenetics of inflammatory bowel disease: a focus on Crohn's disease.
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Rufini S, Ciccacci C, Novelli G, and Borgiani P
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- Drug Resistance genetics, Genetic Markers, Humans, Crohn Disease drug therapy, Crohn Disease genetics, Pharmaceutical Preparations metabolism, Pharmacogenetics, Polymorphism, Single Nucleotide
- Abstract
Crohn's disease is an inflammatory bowel disease showing a high heterogeneity in phenotype and a strong genetic component. The treatment is complex, due to different severity of clinical parameters and to the fact that therapies only permit to control symptoms and to induce remission for short periods. Moreover, all categories of drugs present a great interindividual variability both in terms of efficacy and side effects appearance. For this reason, the identification of specific genomic biomarkers involved in drugs response will be of great clinical utility in order to foresee drug's efficacy and to prevent adverse reactions, permitting a more personalized therapeutic approach. In this review, we focus the attention on the pharmacogenetic studies regarding drugs commonly utilized in Crohn's disease treatment.
- Published
- 2017
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35. Polymorphisms in STAT4, PTPN2, PSORS1C1 and TRAF3IP2 Genes Are Associated with the Response to TNF Inhibitors in Patients with Rheumatoid Arthritis.
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Conigliaro P, Ciccacci C, Politi C, Triggianese P, Rufini S, Kroegler B, Perricone C, Latini A, Novelli G, Borgiani P, and Perricone R
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- Adaptor Proteins, Signal Transducing, Adult, Aged, Arthritis, Rheumatoid genetics, Female, Humans, Male, Middle Aged, Arthritis, Rheumatoid drug therapy, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 2 genetics, Proteins genetics, STAT4 Transcription Factor genetics, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins genetics, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Objective: Rheumatoid Arthritis (RA) is a progressive autoimmune disease characterized by chronic joint inflammation and structural damage. Remission or at least low disease activity (LDA) represent potentially desirable goals of RA treatment. Single nucleotide polymorphisms (SNPs) in several genes might be useful for prediction of response to therapy. We aimed at exploring 4 SNPs in candidate genes (STAT4, PTPN2, PSORS1C1 and TRAF3IP2) in order to investigate their potential role in the response to therapy with tumor necrosis factor inhibitors (TNF-i) in RA patients., Methods: In 171 RA patients we investigated the following SNPs: rs7574865 (STAT4), rs2233945 (PSORS1C1), rs7234029 (PTPN2) and rs33980500 (TRAF3IP2). Remission, LDA, and EULAR response were registered at 6 months and 2 years after initiation of first line TNF-i [Adalimumab (ADA) and Etanercept (ETN)]., Results: STAT4 variant allele was associated with the absence of a good/moderate EULAR response at 2 years of treatment in the whole RA group and in ETN treated patients. The PTPN2 SNP was associated with no good/moderate EULAR response at 6 months in ADA treated patients. Patients carrying PSORS1C1 variant allele did not reach LDA at 6 months in both the whole RA group and ETN treated patients. TRAF3IP2 variant allele was associated with the lack of LDA and remission achievement at 6 months in all RA cohort while an association with no EULAR response at 2 years of treatment occurred only in ETN treated patients., Conclusions: For the first time, we reported that SNPs in STAT4, PTPN2, PSORS1C1, and TRAF3IP2 are associated with response to TNF-i treatment in RA patients; however, these findings should be validated in a larger population., Competing Interests: Giuseppe Novelli serves as Editor for PLOS ONE. This does not alter the authors’ adherence to PLOS ONE Editorial policies and criteria.
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- 2017
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36. Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease.
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D'Arcangelo G, Grossi D, Racaniello M, Cardinale A, Zaratti A, Rufini S, Cutarelli A, Tancredi V, Merlo D, and Frank C
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- 1-Deoxynojirimycin pharmacology, Animals, Disease Models, Animal, Extracellular Signal-Regulated MAP Kinases metabolism, Hippocampus metabolism, Hippocampus physiopathology, Mice, Niemann-Pick Disease, Type C metabolism, Phosphorylation drug effects, Synapses metabolism, 1-Deoxynojirimycin analogs & derivatives, Enzyme Inhibitors pharmacology, Hippocampus drug effects, Neuronal Plasticity drug effects, Niemann-Pick Disease, Type C physiopathology, Synapses drug effects
- Abstract
Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1-/- mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1-/- mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1-/- mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.
- Published
- 2016
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37. Stevens-Johnson syndrome and toxic epidermal necrolysis: an update on pharmacogenetics studies in drug-induced severe skin reaction.
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Rufini S, Ciccacci C, Politi C, Giardina E, Novelli G, and Borgiani P
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- Allopurinol adverse effects, Animals, Drug-Related Side Effects and Adverse Reactions diagnosis, Drug-Related Side Effects and Adverse Reactions genetics, Genetic Predisposition to Disease genetics, Humans, Pharmacogenetics trends, Stevens-Johnson Syndrome diagnosis, Pharmacogenetics methods, Severity of Illness Index, Stevens-Johnson Syndrome genetics
- Abstract
Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, life-threatening drug reactions involving skin and membranes mucous, which are associated with significant morbidity and mortality and triggered, especially by drug exposure. Different studies have demonstrated that drug response is a multifactorial character and that the interindividual variability in this response depends on both environmental and genetic factors. The last ones have a relevant significance. In fact, the identification of new specific genetic markers involved in the response to drugs, will be of great utility to establish a more personalized therapeutic approach and to prevent the appearance of these adverse reactions. In this review, we summarize recent progresses in the Pharmacogenetics studies related to Stevens-Johnson syndrome/toxic epidermal necrolysis reporting the major genetic factors identified in the last years as associated with the disease and highlighting the use of some of these genomic variants in the clinical practice.
- Published
- 2015
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38. A pharmacogenetics study in Mozambican patients treated with nevirapine: full resequencing of TRAF3IP2 gene shows a novel association with SJS/TEN susceptibility.
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Ciccacci C, Rufini S, Mancinelli S, Buonomo E, Giardina E, Scarcella P, Marazzi MC, Novelli G, Palombi L, and Borgiani P
- Subjects
- Adaptor Proteins, Signal Transducing, Adult, Alleles, Anti-HIV Agents therapeutic use, Exons, Genotype, HIV Infections drug therapy, Haplotypes, Humans, Logistic Models, Mozambique, Nevirapine therapeutic use, Odds Ratio, Pharmacogenetics, Polymorphism, Single Nucleotide, Stevens-Johnson Syndrome etiology, Stevens-Johnson Syndrome pathology, Anti-HIV Agents adverse effects, Black People genetics, Genetic Predisposition to Disease, Nevirapine adverse effects, Stevens-Johnson Syndrome genetics, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins genetics
- Abstract
Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe adverse drug reactions, characterized by extensive epidermal detachment and erosions of mucous membrane. SJS/TEN is one of the most serious adverse reactions to Nevirapine (NVP) treatment, commonly used in developing countries as first-line treatment of human immunodeficiency virus infection. In the last years TRAF3IP2 gene variants had been described as associated with susceptibility to several diseases such as psoriasis and psoriatic arthritis. We hypothesized that this gene, involved in immune response and in NF-κB activation, could also be implicated in the SJS/TEN susceptibility. We performed a full resequencing of TRAF3IP2 gene in a population of patients treated with NVP. Twenty-seven patients with NVP-induced SJS/TEN and 78 controls, all from Mozambique, were enrolled. We identified eight exonic and three intronic already described variants. The case/control association analysis highlighted an association between the rs76228616 SNP in exon 2 and the SJS/TEN susceptibility. In particular, the variant allele (C) resulted significantly associated with a higher risk to develop SJS/TEN (p = 0.012 and OR = 3.65 (95% CI 1.33-10.01)). A multivariate analysis by logistic regression confirmed its significant contribution (p = 0.027, OR = 4.39 (95% CI 1.19-16.23)). In conclusion, our study suggests that a variant in TRAF3IP2 gene could be involved in susceptibility to SJS/TEN.
- Published
- 2015
- Full Text
- View/download PDF
39. Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype.
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Ceccarelli F, Perricone C, Borgiani P, Ciccacci C, Rufini S, Cipriano E, Alessandri C, Spinelli FR, Sili Scavalli A, Novelli G, Valesini G, and Conti F
- Subjects
- Animals, Disease Progression, Gene-Environment Interaction, Genetic Predisposition to Disease, Humans, Lupus Erythematosus, Systemic immunology, Lupus Nephritis immunology, Polymorphism, Genetic, Risk, Lupus Erythematosus, Systemic genetics, Lupus Nephritis genetics, Phenotype
- Abstract
Genetic factors exert an important role in determining Systemic Lupus Erythematosus (SLE) susceptibility, interplaying with environmental factors. Several genetic studies in various SLE populations have identified numerous susceptibility loci. From a clinical point of view, SLE is characterized by a great heterogeneity in terms of clinical and laboratory manifestations. As widely demonstrated, specific laboratory features are associated with clinical disease subset, with different severity degree. Similarly, in the last years, an association between specific phenotypes and genetic variants has been identified, allowing the possibility to elucidate different mechanisms and pathways accountable for disease manifestations. However, except for Lupus Nephritis (LN), no studies have been designed to identify the genetic variants associated with the development of different phenotypes. In this review, we will report data currently known about this specific association.
- Published
- 2015
- Full Text
- View/download PDF
40. A multilocus genetic study in a cohort of Italian SLE patients confirms the association with STAT4 gene and describes a new association with HCP5 gene.
- Author
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Ciccacci C, Perricone C, Ceccarelli F, Rufini S, Di Fusco D, Alessandri C, Spinelli FR, Cipriano E, Novelli G, Valesini G, Borgiani P, and Conti F
- Subjects
- Adult, Autoantibodies blood, Case-Control Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Italy, Lupus Erythematosus, Systemic blood, Lupus Erythematosus, Systemic immunology, Male, Middle Aged, Polymorphism, Single Nucleotide, Proteins genetics, RNA, Long Noncoding, Lupus Erythematosus, Systemic genetics, RNA, Untranslated genetics, STAT4 Transcription Factor genetics
- Abstract
Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with complex pathogenesis in which genes and environmental factors are involved. We aimed at analyzing previously identified loci associated with SLE or with other autoimmune and/or inflammatory disorders (STAT4, IL10, IL23R, IRAK1, PSORS1C1, HCP5, MIR146a, PTPN2, ERAP1, ATG16L1, IRGM) in a sample of Italian SLE patients in order to verify or confirm their possible involvement and relative contribution in the disease., Materials and Methods: Two hundred thirty-nine consecutive SLE patients and 278 matched healthy controls were enrolled. Study protocol included complete physical examination, and clinical and laboratory data collection. Nineteen polymorphisms were genotyped by allelic discrimination assays. A case-control association study and a genotype-phenotype correlation were performed., Results: STAT4 was the most associated gene [P = 3 × 10(-7), OR = 2.13 (95% CI: 1.59-2.85)]. IL10 confirmed its association with SLE [rs3024505: P = 0.02, OR = 1.52 (95% CI: 1.07-2.16)]. We describe a novel significant association between HCP5 locus and SLE susceptibility [rs3099844: P = 0.01, OR = 2.06 (95% CI: 1.18-3.6)]. The genotype/phenotype correlation analysis showed several associations including a higher risk to develop pericarditis with STAT4, and an association between HCP5 rs3099844 and anti-Ro/SSA antibodies., Conclusions: STAT4 and IL10 confirm their association with SLE. We found that some SNPs in PSORS1C1, ATG16L1, IL23R, PTPN2 and MIR146a genes can determine particular disease phenotypes. HCP5 rs3099844 is associated with SLE and with anti-Ro/SSA. This polymorphism has been previously found associated with cardiac manifestations of SLE, a condition related with anti-Ro/SSA antibodies. Thus, our results may provide new insights into SLE pathogenesis.
- Published
- 2014
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41. The Kluyveromyces lactis alpha1,6-mannosyltransferase KlOch1p is required for cell-wall organization and proper functioning of the secretory pathway.
- Author
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Uccelletti D, Farina F, Rufini S, Magnelli P, Abeijon C, and Palleschi C
- Subjects
- Amino Acid Sequence, Cell Wall chemistry, Cell Wall metabolism, Chitin analysis, Fungal Proteins chemistry, Fungal Proteins genetics, Fungal Proteins physiology, Gene Deletion, Genetic Complementation Test, Glycosylation, Kluyveromyces physiology, Mannosyltransferases chemistry, Mannosyltransferases genetics, Membrane Glycoproteins analysis, Molecular Sequence Data, Mutation, Sequence Homology, Amino Acid, beta-Glucans analysis, beta-Glucans chemistry, Cell Wall physiology, Kluyveromyces enzymology, Mannosyltransferases physiology, Protein Transport
- Abstract
Mutants of Kluyveromyces lactis denominated vga (vanadate glycosylation affected) bear various combinations of glycosylation and cell-wall defects. The vga3 mutation of K. lactis was mapped in the KlOCH1 gene, encoding the functional homologue of the Saccharomyces cerevisiaealpha1,6-mannosyltransferase. Quantitative analysis of cell-wall components indicated a noticeable increase of chitin and beta1,6-glucans and a severe decrease of mannoproteins in the mutant cells as compared with the wild-type counterparts. Fine-structure determination of the beta1,6-glucan polymer indicated that, in the vga3-1 strain, the beta1,6-glucans are shorter and have more branches than in the wild-type strain. This suggests that cell-wall remodelling changes take place in K. lactis in the presence of glycosylation defects. Moreover, the vga3 cells showed a significantly improved capability of secreting heterologous proteins. Such a capability, accompanied by the highly reduced N-glycosylation, may be of biotechnological interest, especially when hyper-glycosylation of recombinant products must be avoided.
- Published
- 2006
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42. Enhanced secretion of heterologous proteins in Kluyveromyces lactis by overexpression of the GDP-mannose pyrophosphorylase, KlPsa1p.
- Author
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Uccelletti D, Staneva D, Rufini S, Venkov P, and Palleschi C
- Subjects
- Amino Acid Sequence, Cell Wall genetics, Cloning, Molecular, Gene Expression Regulation, Fungal, Genetic Complementation Test, Glycosylation, Hexokinase metabolism, Kluyveromyces genetics, Molecular Sequence Data, Nucleotidyltransferases biosynthesis, Nucleotidyltransferases genetics, Sequence Alignment, Kluyveromyces metabolism, Nucleotidyltransferases metabolism
- Abstract
GDP-mannose is the mannosyl donor for the glycosylation reactions and is synthesized by GDP-mannose pyrophosphorylase from GTP and d-mannose-1-phosphate; in Saccharomyces cerevisiae this enzyme is encoded by the PSA1/VIG9/SRB1 gene. We isolated the Kluyveromyces lactis KlPSA1 gene by complementing the osmotic growth defects of S. cerevisiae srb1/psa1 mutants. KlPsa1p displayed a high degree of similarity with other GDP-mannose pyrophosphorylases and was demonstrated to be the functional homologue of S. cerevisiae Psa1p. Phenotypic analysis of a K. lactis strain overexpressing the KlPSA1 gene revealed changes in the cell wall assembly. Increasing the KlPSA1 copy number restored the defects in O-glycosylation, but not those in N-glycosylation, that occur in K. lactis cells depleted for the hexokinase Rag5p. Overexpression of GDP-mannose pyrophosphorylase also enhanced heterologous protein secretion in K. lactis as assayed by using the recombinant human serum albumin and the glucoamylase from Arxula adeninivorans.
- Published
- 2005
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- View/download PDF
43. Cholesterol perturbing agents inhibit NMDA-dependent calcium influx in rat hippocampal primary culture.
- Author
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Frank C, Giammarioli AM, Pepponi R, Fiorentini C, and Rufini S
- Subjects
- Animals, Calcium antagonists & inhibitors, Cells, Cultured, Fluorescent Antibody Technique, Fluorometry methods, G(M1) Ganglioside metabolism, Hippocampus cytology, Membrane Microdomains drug effects, N-Methylaspartate pharmacology, Neurons cytology, Neurons drug effects, Neurons ultrastructure, Potassium Chloride pharmacology, Rats, Receptors, N-Methyl-D-Aspartate metabolism, Calcium metabolism, Cholesterol metabolism, Cyclodextrins pharmacology, Filipin pharmacology, Hippocampus drug effects, Hippocampus metabolism, N-Methylaspartate antagonists & inhibitors, Neurons metabolism, beta-Cyclodextrins
- Abstract
The present study was carried out to investigate the potential involvement of cholesterol-rich membrane microdomains in the mobilization of calcium induced by NMDA-receptors (NMDA-R). We herein provide evidence that agents interfering with plasma membrane cholesterol (namely, filipin and methyl-beta-cyclodextrin (Cdex)) inhibit the NMDA-stimulated influx of calcium in hippocampal cells in culture. Filipin-treated cells maintained their morphology and were able to respond with a calcium influx to high K(+) challenge, whereas Cdex altered both cellular parameters. These results suggest that the NMDA-R can be located in cholesterol-rich membrane microdomains or alternatively that the mechanisms coupling their dynamics in the post-synaptic membrane are dependent on the integrity of the microdomains.
- Published
- 2004
- Full Text
- View/download PDF
44. Glutamate-induced calcium increase in myotubes depends on up-regulation of a sodium-dependent transporter.
- Author
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Frank C, Giammarioli AM, Falzano L, Fiorentini C, and Rufini S
- Subjects
- 2-Chloroadenosine pharmacology, Amino Acid Transport System X-AG drug effects, Animals, Aspartic Acid analogs & derivatives, Aspartic Acid pharmacology, Biological Transport drug effects, Cell Differentiation drug effects, Cells, Cultured, Cycloheximide pharmacology, Dicarboxylic Acids pharmacology, Glutamate Plasma Membrane Transport Proteins, Mice, Muscle Fibers, Skeletal drug effects, Muscle, Skeletal cytology, Muscle, Skeletal drug effects, Protein Synthesis Inhibitors pharmacology, Purines metabolism, Pyrrolidines pharmacology, Symporters drug effects, Up-Regulation, Amino Acid Transport System X-AG metabolism, Calcium metabolism, Glutamic Acid metabolism, Muscle Fibers, Skeletal metabolism, Muscle, Skeletal metabolism, Symporters metabolism
- Abstract
We report a study on the regulation by 2-chloro adenosine (2CA) of a glutamate (Glu) transporter in myogenic C2C12 cells. Long-term 2CA exposition significantly increased the V(max) of the Glu transporter. Moreover, 2CA-treated cells responded to Glu challenge by a rapid and transient increase in their intracellular calcium level. The above reported effects were totally abolished by treating C2C12 cells with the Na(+)-dependent Glu transporter inhibitors DL-threo-b-hydroxyaspartic acid and L-trans-pyrrolidine-2,4-dicarboxylic acid. We propose that the possible link between the Glu uptake increase and the Glu induction of calcium rise could be the depolarizing currents carried by Na(+) coupled with transporter activity.
- Published
- 2002
- Full Text
- View/download PDF
45. Proliferative effect of ammodytin L from the venom of Vipera ammodytes on 208F rat fibroblasts in culture.
- Author
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Rufini S, Cesaroni MP, Balestro N, and Luly P
- Subjects
- Animals, Bradykinin pharmacology, Calcium pharmacology, Cell Line, DNA biosynthesis, Enzyme Activation, Fibroblasts, Heparin pharmacology, Inositol 1,4,5-Trisphosphate metabolism, Ionomycin pharmacology, Kinetics, Phosphatidylinositol Diacylglycerol-Lyase, Phosphoinositide Phospholipase C, Phospholipases A, Phospholipases A2, Phosphoric Diester Hydrolases metabolism, Rats, Thapsigargin pharmacology, Thymidine metabolism, Viper Venoms isolation & purification, Viperidae, Calcium metabolism, Cell Division drug effects, Viper Venoms pharmacology
- Abstract
Ammodytin L, purified from the venom of Vipera ammodytes, triggers a rapid and dramatic lytic process in myotubes in vitro, as well as in differentiated muscle cells in vivo, through a mechanism that is not well understood. Despite its great sequence similarity to phospholipase A2, it is devoid of any enzyme activity. Data on artificial membranes demonstrating a direct interaction between this toxin and the hydrophobic core of the lipid bilayer suggest that the toxin also acts on the lipid microenvironment in cell membranes. Recent experiments on living cells do not confirm this hypothesis, and a more intricate mechanism is proposed. In vitro, ammodytin L has necrotic effects only in well-differentiated myogenic cells, whereas other cell types such as platelets, red blood cells and lymphocytes show neither morphological nor functional alterations. In this work we demonstrate that rat 208F fibroblasts in culture after ammodytin L challenge increase [3H]thymidine incorporation, indicating that this toxin has a myogenic effect. Moreover, ammodytin L increases intracellular Ca2+ by acting on intracellular stores probably by activating a phosphatidylinositol-specific phospholipase C. Preincubation of the cells with ammodytin L did not prevent the massive Ca2+ release evoked by bradykinin, a phenomenon observed when fibroblasts were incubated with both thapsigargin and ionomycin. Heparin, an agent that inhibits the necrotic effect of the myotoxin in myotubes, also reduces the effect of ammodytin L on DNA synthesis. Heparin inhibits only the late sustained increase in intracellular Ca2+ induced by the toxin.
- Published
- 1996
- Full Text
- View/download PDF
46. The temperature-dependence of human erythrocyte acetylcholinesterase activity is not affected by membrane cholesterol enrichment.
- Author
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Spinedi A, Rufini S, Luly P, and Farias RN
- Subjects
- Detergents pharmacology, Erythrocyte Membrane drug effects, Female, Humans, Kinetics, Lipids blood, Male, Octoxynol, Polyethylene Glycols pharmacology, Temperature, Acetylcholinesterase blood, Cholesterol pharmacology, Erythrocyte Membrane enzymology
- Abstract
The temperature-dependence of both the lipid order parameter (SDPH) and acetylcholinesterase (AChE) activity from native and cholesterol-enriched human erythrocyte membranes was investigated. Cholesterol enrichment abolishes an inflection observed around 30 degrees C in the temperature-dependence of native membrane lipid order parameter, whereas the Arrhenius plot of the enzymic activity is substantially unaffected. These results support the view that the breaks in the Arrhenius plot of the enzyme activity are not related to sudden changes of bulk membrane physical state, but arise from a direct effect of temperature on enzyme conformation.
- Published
- 1988
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