Protein homeostasis is fundamental for cell function and survival because proteins are critical facilitators of all cellular processes. Our goal is to better understand the processes that maintain the fine balance between newly synthesized and old or misfolded proteins, preserving the protein homeostasis and preventing various diseases. Current projects in the laboratory are focused therefore on processes regulating protein lifetime: protein folding and maturation, trafficking, subcellular localization and degradation. Our research explores new ways of investigating the quality control process occurring in the endoplasmic reticulum that facilitates protein secretion towards the Golgi apparatus whilst regulating degradation of misfolded proteins by ERAD pathways.
Protein processing with focus on antigen processing and presentation is currently investigated and aims at determining the exact role of ERAD components in the generation of tyrosinase-derived tumour antigens. Understanding of basic mechanisms of antigen processing and presentation to T cells will provide valuable clues to enhance the efficacy of peptide-based cancer vaccines. Deciphering the pathways mediated by the tyrosinase-related antigen, TRP-2 is another focus of our group aiming at uncovering the potential implications of this antigen in the prognostic and therapy of malignant melanoma.
We develop new tools to extend our knowledge on the role of ERAD in the endoplasmic reticulum of secretory cells. Proinsulin matures in the endoplasmic reticulum of pancreatic β−cells and depending on the ER folding capacity is either secreted or destroyed. Our hypothesis is that up-regulation of ERAD enhancers may alleviate the ER burden in pancreatic β−cells by recruiting misfolded proteins for degradation. To verify this hypothesis we use model β−cells, intact primary islets and animal models with modified ERAD and test the insulin secretion upon glucose-stimulation.
In the next years our research will focus on the molecular mechanisms of the folding and intracellular transport of soluble and membrane bound glycoproteins. In particular, melanoma proteins will be investigated in terms of maturation, degradation and antigen presentation.
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Chiritoiu M, Chiritoiu GN, Munteanu CVA, Pastrama F, Ivessa NE and Petrescu SM. EDEM1 Drives Misfolded Protein Degradation via ERAD and Exploits ER-Phagy as Back-Up Mechanism When ERAD Is Impaired. International Journal of Molecular Sciences, 2020, 10(21): 3468IF=4.10
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Sima LE, Chiritoiu G, Negut I, Grumezescu V, Orobeti S, Munteanu CVA, Sima F, Axente E. Functionalized Graphene Oxide Thin Films for Anti-tumor Drug Delivery to Melanoma Cells. Frontiers in chemistry, 2020, 8: 184IF=3.70
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Visan AI, Popescu-Pelin G, Gherasim O, Mihailescu A, Socol M, Zgura I, Chiritoiu M, Elena Sima L, Antohe F, Ivan L, Vranceanu DM, M Cotruț C, Cristescu R, Socol G. Long-Term Evaluation of Dip-Coated PCL-Blend-PEG Coatings in Simulated Conditions. Polymers, 2020, 12(3)IF=3.42
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Mernea M, Ulăreanu R, Călboreanu O, Chirițoiu G, Cucu D, Mihăilescu DF. N-glycosylation state of TRPM8 protein revealed by terahertz spectroscopy and molecular modelling. Biochimica et biophysica acta. General subjects, 2020, 1864(7): 129580IF=3.42
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Chiritoiu M, Brouwers N, Turacchio G, Pirozzi M, Malhotra V. GRASP55 and UPR Control Interleukin-1β Aggregation and Secretion. Developmental cell, 2019, 49(1): 145-155.e4IF=9.19
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Coman AG, Paun A, Popescu CC, Hădade ND, Hanganu A, Chiritoiu G, Farcasanu IC, Matache M. A novel adaptive fluorescent probe for cell labelling. Bioorg Chem., 2019(92): 103295IF=3.93
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Alexandru Petruta, Cretoiu Sanda, Simona Dima, and Irinel Popescu. CRISPR/Cas9 gene editing in Huh7 and Hepa RG cell lines. Romanian Biotechnological Letters, 2019(24): 216-228IF=0.59
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Villeneuve J, Bassaganyas L, Lepreux S, Chiritoiu M, Costet P, Ripoche J, Malhotra V, Schekman R. Unconventional secretion of FABP4 by endosomes and secretory lysosomes. The Journal of cell biology, 2018, 217(2): 649-665IF=8.89
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Condello S, Sima L, Ivan C, Cardenas H, Schiltz G, Mishra RK, Matei D. Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche. Cancer research, 2018, 78(11): 2990-3001IF=8.38
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Popescu A C, Florian P E, Stan G E, Popescu-Pelin G, Zgura I, Enculescu M, Oktar F N, Trusca R, Sima L E, Roseanu A, Duta L. Physical-chemical characterization and biological assessment of simple and lithium-doped biological-derived hydroxyapatite thin films for a new generation of metallic implants. Applied Surface Science, 2018, 439: 724-735IF=5.15
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Alexandra Gaspar-Pintiliescu, Ana-Maria Seciu, Florin Miculescu, Lucia Moldovan, Elena Ganea, Oana Craciunescu. Enhanced extracellular matrix synthesis using collagen dressings loaded with Artemisia absinthium plant extract, 2018(Journal of Bioactive and Compatible Polymers)
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Nwani NG, Sima LE, Nieves-Neira W, Matei D. Targeting the Microenvironment in High Grade Serous Ovarian Cancer. Cancers, 2018, 10(8)
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Deftu AF, Filippi A, Shibsaki K, Gheorghe RO, Chiritoiu M, Ristoiu V. Chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-X-C motif) ligand 2 (CXCL2) modulate the activity of TRPV1+/IB4+ cultured rat dorsal root ganglia neurons upon short-term and acute application. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2017, 68(3): 385-395IF=2.48
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Uta M, Sima LE, Hoffmann P, Dinca V, Branza-Nichita N. Development of a DsRed-expressing HepaRG cell line for real-time monitoring of hepatocyte-like cell differentiation by fluorescence imaging, with application in screening of novel geometric microstructured cell growth substrates. Biomedical microdevices, 2017, 19(1): 3IF=2.08
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A Visan, R Cristescu, N Stefan, M Miroiu, C Nita, M Socol, C Florica, O Rasoga, I Zgura, LE Sima, M Chiritoiu, MC Chifiriuc, AM Holban, IN Mihailescu, G Socol. Antimicrobial polycaprolactone/polyethylene glycol embedded lysozyme coatings of Ti implants for osteoblast functional properties in tissue engineering. Applied Surface Science, 2017, 417: 234-243
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O.RașogaaL.SimabM.ChirițoiubG.Popescu-PelincO.FufăcdV.GrumezescucdM.SocolaA.StănculescuaI.ZgurăaG.Socolc. Biocomposite coatings based on Poly (3-hydroxybutyrate-co-3-hydroxyvalerate)/calcium phosphates obtained by MAPLE for bone tissue engineering. Applied Surface Science, 2017, 417: 204-212
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ROXANA-OLIMPIA GHEORGHE 1, ALEXANDRA SOCA 1, MARIOARA CHIRIȚOIU 2, ALEXANDRU-FLORIAN DEFTU 1, MARIA-LUIZA FLONTA 1, VIOLETA RISTOIU1 *. Long-term exposure to CXCL2 has cytotoxic effects on HEK293T cells stably expressing TRPV1. Romanian Biotechnological letters, 2017
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Ulăreanu R, Chiriţoiu G, Cojocaru F, Deftu A, Ristoiu V, Stănică L, Mihăilescu DF, Cucu D. N-glycosylation of the transient receptor potential melastatin 8 channel is altered in pancreatic cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2017, 39(8): 1010428317720940
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Grumezescu V, Holban AM, Sima LE, Chiritoiu MB, Chiritoiu GN, Grumezescu AM, Ivan L, Safciuc F, Antohe F, Florica C, Luculescu CR, Chifiriuc MC, Socol G. Laser deposition of poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) - lysozyme microspheres based coatings with anti-microbial properties. International journal of pharmaceutics, 2017, 521(1-2): 184-195
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Sima LE. Extracellular Signals for Guiding Mesenchymal Stem Cells Osteogenic Fate. Current stem cell research & therapy, 2017, 12(2): 139-144
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Popa IL, Milac AL, Sima LE, Alexandru PR, Pastrama F, Munteanu CV, Negroiu G. Cross-talk between Dopachrome Tautomerase and Caveolin-1 Is Melanoma Cell Phenotype-specific and Potentially Involved in Tumor Progression. The Journal of biological chemistry, 2016, 291(24): 12481-500IF=4.12
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Chiritoiu GN, Jandus C, Munteanu CV, Ghenea S, Gannon PO, Romero P, Petrescu SM. Epitope located N-glycans impair the MHC-I epitope generation and presentation. Electrophoresis, 2016, 37(11): 1448-60IF=2.74
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Alexandra Gaspar, Daniel Constantin, Ana-Maria Seciu, Lucia Moldovan, Oana Craciunescu, Elena Ganea. Human adipose-derived stem cells differentiation into epidermal cells and interaction with human keratinocytes in coculture, 2016(Turkish Journal of Biology)
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Zurac S, Neagu M, Constantin C, Cioplea M, Nedelcu R, Bastian A, Popp C, Nichita L, Andrei R, Tebeica T, Tanase C, Chitu V, Caruntu C, Ghita M, Popescu C, Boda D, Mastalier B, Maru N, Daha C, Andreescu B, Marinescu I, Rebosapca A, Staniceanu F, Negroiu G, Ion DA, Nikitovic D, Tzanakakis GN, Spandidos DA, Tsatsakis AM. Variations in the expression of TIMP1, TIMP2 and TIMP3 in cutaneous melanoma with regression and their possible function as prognostic predictors. Oncology letters, 2016, 11(5): 3354-3360
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GABRIELA N. CHIRIȚOIU, CRISTIAN V.A. MUNTEANU, NICULINA MITREA. COMBINING HETEROLOGOUS BACTERIAL EXPRESSION SYSTEM WITH AFFINITY CHROMATOGRAPHY PURIFICATION TO OBTAIN NATIVE MOUSE TYROSINASE. Farmacia, 2015, 2(63): 254-261IF=1.16
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Ulmeanu M, Sima LE, Ursescu D, Enculescu M, Bazan X, Quintana I. Cell adhesion response on femtosecond laser initiated liquid assisted silicon surface. Current topics in medicinal chemistry, 2014, 14(5): 624-9IF=3.40
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Cucu D, Chiritoiu G, Petrescu S, Babes A, Stanica L, Duda DG, Horii A, Dima SO, Popescu I. Characterization of functional transient receptor potential melastatin 8 channels in human pancreatic ductal adenocarcinoma cells. Pancreas, 2014, 43(5): 795-800IF=2.96
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Ioana Popa*, Elena Ganea, and Stefana M. Petrescu. Expression and subcellular localization of RAGE in melanoma cells. Biochemistry and Cell Biology, 2014, 2(92): 127-136
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Dinca V, Florian PE, Sima LE, Rusen L, Constantinescu C, Evans RW, Dinescu M, Roseanu A. MAPLE-based method to obtain biodegradable hybrid polymeric thin films with embedded antitumoral agents. Biomedical microdevices, 2014, 16(1): 11-21
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Corotchi MC, Popa MA, Remes A, Sima LE, Gussi I, Lupu Plesu M. Isolation method and xeno-free culture conditions influence multipotent differentiation capacity of human Wharton's jelly-derived mesenchymal stem cells. Stem cell research & therapy, 2013, 4(4): 81IF=4.63
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Sima LE, Buruiana EC, Buruiana T, Matei A, Epurescu G, Zamfirescu M, Moldovan A, Petrescu SM, Dinescu M. Dermal cells distribution on laser-structured ormosils. Journal of tissue engineering and regenerative medicine, 2013, 7(2): 129-38
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Filimon A, Sima LE, Appelhans D, Voit B, Negroiu G. Internalization and intracellular trafficking of poly(propylene imine) glycodendrimers with maltose shell in melanoma cells. Current medicinal chemistry, 2012, 19(29): 4955-68IF=4.07
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Ivan V, Martinez-Sanchez E, Sima LE, Oorschot V, Klumperman J, Petrescu SM, van der Sluijs P. AP-3 and Rabip4' coordinately regulate spatial distribution of lysosomes. PloS one, 2012, 7(10): e48142IF=3.73
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Florian P, Macovei A, Sima L, Nichita N, Mattsby-Baltzer I, Roseanu A. Endocytosis and trafficking of human lactoferrin in macrophage-like human THP-1 cells (1). Biochemistry and cell biology = Biochimie et biologie cellulaire, 2012, 90(3): 449-55IF=2.92
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Ioana Popa*, Elena Ganea, Stefana Petrescu. RAGE over AGEs and DAMPs. Romanian Journal of Biochemistry,, 2012, 2(49): 195-210
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Zurac S, Negroiu G, Petrescu S, Andrei R, Tebeica T, Popp C, Musţată R, Neagu M, Constantin C, Solovan C, Chiţu V, Reboşapcă A, Andreescu B, Marinescu I, Stăniceanu F. Spectrum of morphologic alterations of regression in cutaneous melanoma--potential for improving disease prognosis. Romanian journal of internal medicine = Revue roumaine de medecine interne, 2012, 50(2): 145-53
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Marin MB, Ghenea S, Spiridon LN, Chiritoiu GN, Petrescu AJ, Petrescu SM. Tyrosinase degradation is prevented when EDEM1 lacks the intrinsically disordered region. PloS one, 2012, 7(8): e42998
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Cioaca D, Ghenea S, Spiridon LN, Marin M, Petrescu AJ, Petrescu SM. C-terminus glycans with critical functional role in the maturation of secretory glycoproteins. PloS one, 2011, 6(5): e19979IF=4.09
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Sima F, Mutlu EC, Eroglu MS, Sima LE, Serban N, Ristoscu C, Petrescu SM, Oner ET, Mihailescu IN. Levan nanostructured thin films by MAPLE assembling. Biomacromolecules, 2011, 12(6): 2251-6
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Sima F, Ristoscu C, Caiteanu D, Mihailescu CN, Stefan N, Mihailescu IN, Prodan G, Ciupina V, Palcevskis E, Krastins J, Sima LE, Petrescu SM. Biocompatibility and bioactivity enhancement of Ce stabilized ZrO(2) doped HA coatings by controlled porosity change of Al(2) O(3) substrates. Journal of biomedical materials research. Part B, Applied biomaterials, 2011, 96(2): 218-24
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Sima F, Axente E, Ristoscu C, Mihailescu IN, Kononenko TV, Nagovitsin IA, Chudinova G, Konov VI, Socol M, Enculescu I, Sima LE, Petrescu SM. Tailoring immobilization of immunoglobulin by excimer laser for biosensor applications. Journal of biomedical materials research. Part A, 2011, 96(2): 384-94
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Sima LE, Stan GE, Morosanu CO, Melinescu A, Ianculescu A, Melinte R, Neamtu J, Petrescu SM. Differentiation of mesenchymal stem cells onto highly adherent radio frequency-sputtered carbonated hydroxylapatite thin films. Journal of biomedical materials research. Part A, 2010, 95(4): 1203-14IF=3.04
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Sima LE, Filimon A, Piticescu RM, Chitanu GC, Suflet DM, Miroiu M, Socol G, Mihailescu IN, Neamtu J, Negroiu G. Specific biofunctional performances of the hydroxyapatite-sodium maleate copolymer hybrid coating nanostructures evaluated by in vitro studies. Journal of materials science. Materials in medicine, 2009, 20(11): 2305-16
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Zurac S, Andrei R, Petsakos G, Nichita L, Bastian A, Micu G, Gramadă E, Popp C, Stăniceanu F, Petrescu S, Negroiu G, Giurcăneanu D, Chiţu V. Cutaneous metastases of malignant melanoma--how difficult can it be?. Romanian journal of internal medicine = Revue roumaine de medecine interne, 2008, 46(4): 375-8
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Negroiu G, Dwek RA, Petrescu SM. Tyrosinase-related protein-2 and -1 are trafficked on distinct routes in B16 melanoma cells. Biochemical and biophysical research communications, 2005, 328(4): 914-21
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Neeft M, Wieffer M, de Jong AS, Negroiu G, Metz CH, van Loon A, Griffith J, Krijgsveld J, Wulffraat N, Koch H, Heck AJ, Brose N, Kleijmeer M, van der Sluijs P. Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. Molecular biology of the cell, 2005, 16(2): 731-41
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Negroiu G, Dwek RA, Petrescu SM. The inhibition of early N-glycan processing targets TRP-2 to degradation in B16 melanoma cells. The Journal of biological chemistry, 2003, 278(29): 27035-42
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Negroiu G, Dwek RA, Petrescu SM. Folding and maturation of tyrosinase-related protein-1 are regulated by the post-translational formation of disulfide bonds and by N-glycan processing. The Journal of biological chemistry, 2000, 275(41): 32200-7
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Branza-Nichita N, Petrescu AJ, Negroiu G, Dwek RA, Petrescu SM. N-glycosylation processing and glycoprotein folding-lessons from the tyrosinase-related proteins. Chemical reviews, 2000, 100(12): 4697-712
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Petrescu SM, Branza-Nichita N, Negroiu G, Petrescu AJ, Dwek RA. Tyrosinase and glycoprotein folding: roles of chaperones that recognize glycans. Biochemistry, 2000, 39(18): 5229-37
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Branza-Nichita N, Negroiu G, Petrescu AJ, Garman EF, Platt FM, Wormald MR, Dwek RA, Petrescu SM. Mutations at critical N-glycosylation sites reduce tyrosinase activity by altering folding and quality control. The Journal of biological chemistry, 2000, 275(11): 8169-75
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Negroiu G, Branza-Nichita N, Costin GE, Titu H, Petrescu AJ, Dwek RA, Petrescu SM. Investigation of the intracellular transport of tyrosinase and tyrosinase related protein (TRP)-1. The effect of endoplasmic reticulum (ER)-glucosidases inhibition. Cellular and molecular biology (Noisy-le-Grand, France), 1999, 45(7): 1001-10
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Negroiu G, Branza-Nichita N, Petrescu AJ, Dwek RA, Petrescu SM. Protein specific N-glycosylation of tyrosinase and tyrosinase-related protein-1 in B16 mouse melanoma cells. The Biochemical journal, 1999, 344 Pt 3: 659-65
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Glant TT, Buzás EI, Finnegan A, Negroiu G, Cs-Szabó G, Mikecz K. Critical roles of glycosaminoglycan side chains of cartilage proteoglycan (aggrecan) in antigen recognition and presentation. Journal of immunology (Baltimore, Md. : 1950), 1998, 160(8): 3812-9
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Zapun A, Petrescu SM, Rudd PM, Dwek RA, Thomas DY, Bergeron JJ. Conformation-independent binding of monoglucosylated ribonuclease B to calnexin. Cell, 1997, 88(1): 29-38
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Petrescu AJ, Butters TD, Reinkensmeier G, Petrescu S, Platt FM, Dwek RA, Wormald MR. The solution NMR structure of glucosylated N-glycans involved in the early stages of glycoprotein biosynthesis and folding. The EMBO journal, 1997, 16(14): 4302-10
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Brennan FR, Mikecz K, Buzás EI, Ragasa D, Cs-Szabó G, Negroiu G, Glant TT. Antigen-specific B cells present cartilage proteoglycan (aggrecan) to an autoreactive T cell hybridoma derived from a mouse with proteoglycan-induced arthritis. Clinical and experimental immunology, 1995, 101(3): 414-21
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Buzás EI, Brennan FR, Mikecz K, Garzó M, Negroiu G, Holló K, Cs-Szabó G, Pintye E, Glant TT. A proteoglycan (aggrecan)-specific T cell hybridoma induces arthritis in BALB/c mice. Journal of immunology (Baltimore, Md. : 1950), 1995, 155(5): 2679-87
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Brennan FR, Negroiu G, Buzás EI, Fülöp C, Holló K, Mikecz K, Glant TT. Presentation of cartilage proteoglycan to a T cell hybridoma derived from a mouse with proteoglycan-induced arthritis. Clinical and experimental immunology, 1995, 100(1): 104-10
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Mirancea N, Mirancea D, Caloianu-Iordăchel M, Toader G, Moldovan L, Negroiu G. The action of the collagen-Fe2+ complex at tissular level. Morphologie et embryologie, 1989, 35(1): 59-61
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Proteomics Technologies and Applications in Mass Spectrometry for Cancer Biomarkers, 2019(5), InTechOpen: 477
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A.Milac, G. Negroiu. Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments in The Multiple Roles of Tyrosinase-Related Protein-2/Ldopachrome Tautomerase in Melanoma, 2018
Biotehnologii Celulare si Moleculare cu Aplicatii in Medicina
2010-2013
Acronym: Programul Postdoctoral
Project director: Stefana-Maria Petrescu
Programul Postdoctoral "Biotehnologii Celulare si Moleculare cu Aplicatii in Medicina", se adreseaza tinerilor cu diploma de doctor in biologie, chimie, fizica, medicina si informatica - interesati de burse de cercetare Post Doctorala la standarde europene.
In vitro evaluation of potential biomedical strategies aimed to prevent bone loss during spaceflight
2017-2019
Acronym: SPACEBONE
Project director: Stefana-Maria Petrescu
Bone loss represents one of the most important health problems experienced by Space travelling astronauts. Microgravity produces deterioration of the skeleton due to lack of mechanical loading thus affecting both muscle and bones. Tendons stiffness decreases, muscle fibres atrophies and attenuates their metabolic capacity, whileprogressive cartilage loss occurs.
Microfluidic assay of FGF2 therapeutic administration for bone regeneration
2017-2019
Acronym: μFGF2bone
Project director: Gabriela Chiritoiu
Musculoskeletal disorders affect 1 in 7 people and fractures alone affect 1 in 50 people annually while 10% of bone injuries fail to heal. Our present proposal aims to test for the first time the potential of fibroblast growth factor-2 (FGF2), to be administered as a stimulatory drug to enhance bone regeneration.
Platforma robusta pentru descoperirea de medicamente anti-diabetice
2016-2019
Acronym: PLATFORMDIAB
Project director: Florentina Pena
Societatea contemporana se afla in mijlocul unei epidemii globale de diabet zaharat tip 2. Aceasta boala este caracterizata de concentratii patologic crescute de glucoza in sangele pacientilor datorita productiei, secretiei si utilizarii inadecvate a insulinei - hormonul principal care regleaza concentratia de glucoza serica. Ne propunem sa generam linii reporter stabile ce pot fi utilizate pentru cuantificarea insulinei secretate.
Development of a fluorescence-based technology to screen for RAGE-ligand binding inhibitors
2016-2020
Acronym: FLUORORAGE
Project director: Ioana Popa
The receptor for advanced glycation end-products (RAGE) and its ligands are important players in pathological conditions such as diabetes, neurodegenerative diseases, and cancers. RAGE is a cell surface molecule of the immunoglobulin superfamily. Alternatively spliced variants lacking either only the intracellular domain or both the intracellular and the transmembrane domains are also expressed in some tissues.
Role of the ERAD pathway in the degradation of tyrosinase and production of antigenic peptides in human melanoma
2012-2015
Acronym: TYRPRES
Project director: Stefana-Maria Petrescu
A detailed knowledge of the mechanisms of antigen processing and presentation is essential to optimize cancer vaccination. known as Endoplasmic Reticulum Associated Degradation (ERAD). Non cytosolic misfolded proteins, synthesized at the endoplasmic reticulum are degraded to peptides by a complex machinery Cancer immunotherapy aims at harnessing the resources of the immune system to treat cancer.
Selectia cailor de degradare a proteinelor in patogeneza bolilor umane
2013-2015
Acronym: PRODEGRAD
Project director: Stefana-Maria Petrescu
A considerable fraction of all newly synthesized secretory polypeptides fail to attain their native conformation due to mutations, transcriptional and translational errors, folding defects or endoplasmic reticulum (ER) stress conditions.
Romanian Academy