Publications by authors named "Viviana Costa"

34 Publications

Flavonoids in Bone Erosive Diseases: Perspectives in Osteoporosis Treatment.

Trends Endocrinol Metab 2021 02 4;32(2):76-94. Epub 2020 Dec 4.

IRCCS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche - SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, Bologna, Italy.

Imbalance of bone homeostasis, with excessive bone resorption compared with bone formation, leads to the development of progressive osteopenia leading to lower bone resistance to load, with consequent pain and functional limitations. Phytochemicals with therapeutic and preventive effects against bone resorption have recently received increasing attention since they are potentially more suitable for long-term use than traditional therapeutic chemical compounds. In this systematic review of the literature of the past 5 years, comprehensive information is provided on flavonoids with potential antiresorption and pro-osteogenic effects. It aims to highlight the molecular mechanisms of these molecules, often epigenetic, and their possible pharmacological use, which is of great importance for the prevention and treatment of osteoporosis (OP).
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http://dx.doi.org/10.1016/j.tem.2020.11.007DOI Listing
February 2021

Multiple Myeloma-Derived Extracellular Vesicles Induce Osteoclastogenesis through the Activation of the XBP1/IRE1α Axis.

Cancers (Basel) 2020 Aug 4;12(8). Epub 2020 Aug 4.

IRCSS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche-SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, 40136 Bologna, Italy.

Bone disease severely affects the quality of life of over 70% of multiple myeloma (MM) patients, which daily experience pain, pathological fractures, mobility issues and an increased mortality. Recent data have highlighted the crucial role of the endoplasmic reticulum-associated unfolded protein response (UPR) in malignant transformation and tumor progression; therefore, targeting of UPR-related molecules may open novel therapeutic avenues. Endoplasmic reticulum (ER) stress and UPR pathways are constitutively activated in MM cells, which are characterized by an increased protein turnover as a consequence of high production of immunoglobulins and high rates of protein synthesis. A great deal of scientific data also evidenced that a mild activation of UPR pathway can regulate cellular differentiation. Our previous studies revealed that MM cell-derived small extracellular vesicle (MM-EV) modulated osteoclasts (OCs) function and induced OCs differentiation. Here, we investigated the role of the UPR pathway, and in particular of the IRE1α/XBP1 axis, in osteoclastogenesis induced by MM-EVs. By proteomic analysis, we identified UPR signaling molecules as novel MM-EV cargo, prompting us to evaluate the effects of the MM-EVs on osteoclastogenesis through UPR pathway. MM-EVs administration in a murine macrophage cell line rapidly induced activation of IRE1α by phosphorylation in S724; accordingly, Xbp1 mRNA splicing was increased and the transcription of NFATc1, a master transcription factor for OCs differentiation, was activated. Some of these results were also validated using both human primary OC cultures and MM-EVs from MM patients. Notably, a chemical inhibitor of IRE1α (GSK2850163) counteracted MM-EV-triggered OC differentiation, hampering the terminal stages of OCs differentiation and reducing bone resorption.
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http://dx.doi.org/10.3390/cancers12082167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465175PMC
August 2020

Bone's Response to Mechanical Loading in Aging and Osteoporosis: Molecular Mechanisms.

Calcif Tissue Int 2020 10 24;107(4):301-318. Epub 2020 Jul 24.

IRCCS Istituto Ortopedico Rizzoli, SC Scienze e Tecnologie Chirurgiche - SS Piattaforma Scienze Omiche per Ortopedia Personalizzata, Via Di Barbiano, 1/10, 40136, Bologna, Italy.

Mechanotransduction is pivotal in the maintenance of homeostasis in different tissues and involves multiple cell signaling pathways. In bone, mechanical stimuli regulate the balance between bone formation and resorption; osteocytes play a central role in this regulation. Dysfunctions in mechanotransduction signaling or in osteocytes response lead to an imbalance in bone homeostasis. This alteration is very relevant in some conditions such as osteoporosis and aging. Both are characterized by increased bone weakness due to different causes, for example, the increase of osteocyte apoptosis that cause an alteration of fluid space, or the alteration of molecular pathways. There are intertwined yet very different mechanisms involved among the cell-intrinsic effects of aging on bone, the cell-intrinsic and tissue-level effects of estrogen/androgen withdrawal on bone, and the effects of reduced mechanical loading on bone, which are all involved to some degree in how aged bone fails to respond properly to stress/strain compared to younger bone. This review aims at clarifying how the cellular and molecular pathways regulated and induced in bone by mechanical stimulation are altered with aging and in osteoporosis, to highlight new possible targets for antiresorptive or anabolic bone therapeutic approaches.
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http://dx.doi.org/10.1007/s00223-020-00724-0DOI Listing
October 2020

Structural and spectroscopic studies of a nanostructured silicon-perovskite interface.

Nanoscale 2020 Feb;12(7):4498-4505

Department of Chemistry and Biochemistry, Texas Christian University, TCU Box 298860, Fort Worth, Texas 76129, USA.

While extensively investigated in thin film form for energy materials applications, this work investigates the formation of APbBr3 structures (A = CH3NH3+ (MA), Cs+) in silicon and oxidized silicon nanotubes (SiNTs) with varying inner diameter. We carefully control the extent of oxidation of the nanotube host and correlate the relative Si/Si oxide content in a given nanotube host with the photoluminescence quantum efficiency (PLQE) of the perovskite. Complementing these measurements is an evaluation of average PL lifetimes of a given APbBr3 nanostructure, as evaluated by time-resolved confocal photoluminescence measurements. Increasing Si (decreasing oxide) content in the nanotube host results in a sensitive reduction of MAPbBr3 PLQE, with a concomitant decrease in average lifetime (τave). We interpret these observations in terms of decreased defect passivation by a lower concentration of oxide species surrounding the perovskite. In addition, we show that the use of selected nanotube templates leads to more stable perovskite PL in air over time (weeks). Taken in concert, such fundamental observations have implications for interfacial carrier interactions in tandem Si/perovskite photovoltaics.
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http://dx.doi.org/10.1039/c9nr09622aDOI Listing
February 2020

What Is the Role of Interleukins in Breast Cancer Bone Metastases? A Systematic Review of Preclinical and Clinical Evidence.

Cancers (Basel) 2019 Dec 13;11(12). Epub 2019 Dec 13.

Laboratory Preclinical and Surgical Studies, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.

Breast cancer cells produce stimulators of bone resorption known as interleukins (ILs). However, data on the functional roles of ILs in the homing of metastatic breast cancer to bone are still fragmented. A systematic search was carried out in three databases (PubMed, Scopus, Web of Science Core Collection) to identify preclinical reports, and in three clinical registers (ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, European Union (EU) Clinical Trials Register) to identify clinical trials, from 2008 to 2019. Sixty-seven preclinical studies and 11 clinical trials were recognized as eligible. Although preclinical studies identified specific key ILs which promote breast cancer bone metastases, which have pro-metastatic effects (e.g., IL-6, IL-8, IL-1β, IL-11), and whose inhibition also shows potential preclinical therapeutic effects, the clinical trials focused principally on ILs (IL-2 and IL-12), which have an anti-metastatic effect and a potential to generate a localized and systemic antitumor response. However, these clinical trials are yet to post any results or conclusions. This inconsistency indicates that further studies are necessary to further develop the understanding of cellular and molecular relations, as well as signaling pathways, both up- and downstream of ILs, which could represent a novel strategy to treat tumors that are resistant to standard care therapies for patients affected by breast cancer bone disease.
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http://dx.doi.org/10.3390/cancers11122018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966526PMC
December 2019

MiR-33a Controls hMSCS Osteoblast Commitment Modulating the Yap/Taz Expression Through EGFR Signaling Regulation.

Cells 2019 11 22;8(12). Epub 2019 Nov 22.

IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy..

Mesenchymal stromal cells (hMSCs) display a pleiotropic function in bone regeneration. The signaling involved in osteoblast commitment is still not completely understood, and that determines the failure of current therapies being used. In our recent studies, we identified two miRNAs as regulators of hMSCs osteoblast differentiation driving hypoxia signaling and cytoskeletal reorganization. Other signalings involved in this process are epithelial to mesenchymal transition (EMT) and epidermal growth factor receptor (EGFR) signalings through the regulation of Yes-associated protein (YAP)/PDZ-binding motif (TAZ) expression. In the current study, we investigated the role of miR-33a family as a (i) modulator of YAP/TAZ expression and (ii) a regulator of EGFR signaling during osteoblast commitments. Starting from the observation on hMSCs and primary osteoblast cell lines (Nh-Ost) in which EMT genes and miR-33a displayed a specific expression, we performed a gain and loss of function study with miR-33a-5p and 3p on hMSCs cells and Nh-Ost. After 24 h of transfections, we evaluated the modulation of EMT and osteoblast genes expression by qRT-PCR, Western blot, and Osteoimage assays. Through bioinformatic analysis, we identified YAP as the putative target of miR-33a-3p. Its role was investigated by gain and loss of function studies with miR-33a-3p on hMSCs; qRT-PCR and Western blot analyses were also carried out. Finally, the possible role of EGFR signaling in YAP/TAZ modulation by miR-33a-3p expression was evaluated. Human MSCs were treated with EGF-2 and EGFR inhibitor for different time points, and qRT-PCR and Western blot analyses were performed. The above-mentioned methods revealed a balance between miR-33a-5p and miR-33a-3p expression during hMSCs osteoblast differentiation. The human MSCs phenotype was maintained by miR-33a-5p, while the maintenance of the osteoblast phenotype in the Nh-Ost cell model was permitted by miR-33a-3p expression, which regulated YAP/TAZ through the modulation of EGFR signaling. The inhibition of EGFR blocked the effects of miR-33a-3p on YAP/TAZ modulation, favoring the maintenance of hMSCs in a committed phenotype. A new possible personalized therapeutic approach to bone regeneration was discussed, which might be mediated by customizing delivery of miR-33a in simultaneously targeting EGFR and YAP signaling with combined use of drugs.
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http://dx.doi.org/10.3390/cells8121495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953103PMC
November 2019

Improvement of osteogenic differentiation of human mesenchymal stem cells on composite poly l-lactic acid/nano-hydroxyapatite scaffolds for bone defect repair.

J Biosci Bioeng 2020 Feb 7;129(2):250-257. Epub 2019 Sep 7.

IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano 1/10, Bologna 40136, Italy.

Tissue engineering offers new approaches to repair bone defects, which cannot be repaired physiologically, developing scaffolds that mimic bone tissue architecture. Furthermore, biomechanical stimulation induced by bioreactor, provides biomechanical cues that regulate a wide range of cellular events especially required for cellular differentiation and function. The improvement of human mesenchymal stem cells (hMSCs) colonization in poly-l-lactic-acid (PLLA)/nano-hydroxyapatite (nHA) composite scaffold was evaluated in terms of cell proliferation (dsDNA content), bone differentiation (gene expression and protein synthesis) and ultrastructural analysis by comparing static (s3D) and dynamic (d3D) 3D culture conditions at 7 and 21 days. The colonization rate of hMSCs and osteogenic differentiation were amplified by d3D when physical stimulation was provided by a perfusion bioreactor. Increase in dsDNA content (p < 0.0005), up-regulation of RUNX2, ALPL, SPP1 (p < 0.0005) and SOX9 (p < 0.005) gene expression, and more calcium nodule formation (p < 0.0005) were observed in d3D cultures in comparison to s3D ones over time. Dynamic 3D culture, mimicking the mechanical signals of bone environment, improved significantly osteogenic differentiation of hMSCs on PLLA/nHA scaffold, without the addition of growth factors, confirming this composite scaffold suitable for bone regeneration.
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http://dx.doi.org/10.1016/j.jbiosc.2019.08.001DOI Listing
February 2020

Osteosarcoma cell-derived exosomes affect tumor microenvironment by specific packaging of microRNAs.

Carcinogenesis 2020 07;41(5):666-677

IRCCS Istituto Ortopedico Rizzoli, Laboratory of Preclinical and Surgical Studies, Bologna, Italy.

Bone microenvironment provides growth and survival signals essential for osteosarcoma (OS) initiation and progression. OS cells regulate communications inside tumor microenvironment through different ways and, among all, tumor-derived exosomes support cancer progression and metastasis. To define the contribution of OS-derived exosomes inside the microenvironment, we investigated the effects induced in bone remodeling mechanism and tumor angiogenesis. We demonstrated that exosomes promoted osteoclasts differentiation and bone resorption activity. Furthermore, exosomes potentiated tube formation of endothelial cells and increased angiogenic markers expression. We therefore investigated the micro RNA (miRNA) cargo from exosomes and their parental cells by performing small RNA sequencing through NGS Illumina platform. Hierarchical clustering highlighted a unique molecular profile of exosomal miRNA; bioinformatic analysis by DIANA-mirPath revealed that miRNAs identified take part in various biological processes and carcinogenesis. Among these miRNAs, some were already known for their involvement in the tumor microenvironment establishment, as miR-148a and miR-21-5p. Enforced expression of miR-148a and miR-21-5p in Raw264.7 and hTert immortalized umbilical vein endothelial cells recapitulated the effects induced by exosomes. Overall, our study highlighted the importance of OS exosomes in tumor microenvironment also by a specific packaging of miRNAs.
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http://dx.doi.org/10.1093/carcin/bgz130DOI Listing
July 2020

Focused Ultrasound Effects on Osteosarcoma Cell Lines.

Biomed Res Int 2019 19;2019:6082304. Epub 2019 May 19.

IRCCS Istituto Ortopedico Rizzoli, Via di Barbiano, 1/10 - 40136 Bologna, Italy.

MRI guided Focused Ultrasound (MRgFUS) has shown to be effective therapeutic modality for non-invasive clinical interventions in ablating of uterine fibroids, in bone metastasis palliative treatments, and in breast, liver, and prostate cancer ablation. MRgFUS combines high intensity focused ultrasound (HIFU) with MRI images for treatment planning and real time thermometry monitoring, thus enabling non-invasive ablation of tumor tissue. Although in the literature there are several studies on the Ultrasound (US) effects on cell in culture, there is no systematic evidence of the biological effect of Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) treatment on osteosarcoma cells, especially in lower dose regions, where tissues receive sub-lethal acoustic power. The effect of MRgFUS treatment at different levels of acoustic intensity (15.5-49 W/cm) was investigated on Mg-63 and Saos-2 cell lines to evaluate the impact of the dissipation of acoustic energy delivered outside the focal area, in terms of cell viability and osteogenic differentiation at 24 h, 7 days, and 14 days after treatment. Results suggested that the attenuation of FUS acoustic intensities from the focal area (higher intensities) to the "far field" (lower intensities) zones might determine different osteosarcoma cell responses, which range from decrease of cell proliferation rates (from 49 W/cm to 38.9 W/cm) to the selection of a subpopulation of heterogeneous and immature living cells (from 31.1 W/cm to 15.5 W/cm), which can clearly preserve bone tumor cells.
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http://dx.doi.org/10.1155/2019/6082304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545756PMC
December 2019

miR-31-5p Is a LIPUS-Mechanosensitive MicroRNA that Targets HIF-1α Signaling and Cytoskeletal Proteins.

Int J Mol Sci 2019 Mar 28;20(7). Epub 2019 Mar 28.

IRCCS Istituto Ortopedico Rizzoli, Laboratory of Preclinical and Surgical Studies, 40136 Bologna, Italy.

The roles of low-intensity pulsed ultrasound (LIPUS) and microRNAs (miRNAs) on hMSCs commitments have already been investigated; however, the effects of the application of their co-treatments in an in vitro cell model are still unknown. Our previous studies demonstrated that (i) LIPUS modulated hMSCs cytoskeletal organization and (ii) miRNA-675-5p have a role in HIF-1α signaling modulation during hMSCs osteoblast commitment. We investigated for the first time the role of LIPUS as promoter tool for miRNA expression. Thanks to bioinformatic analysis, we identified miR-31-5p as a LIPUS-induced miRNA and investigated its role through in vitro studies of gain and loss of function. Results highlighted that LIPUS stimulation induced a hypoxia adaptive cell response, which determines a reorganization of cell membrane and cytoskeleton proteins. MiR-31-5p gain and loss of function studies, demonstrated as miR-31-5p overexpression, were able to induce hypoxic and cytoskeletal responses. Moreover, the co-treatments LIPUS and miR-31-5p inhibitor abolished the hypoxic responses including angiogenesis and the expression of Rho family proteins. MiR-31-5p was identified as a LIPUS-mechanosensitive miRNAs and may be considered a new therapeutic option to promote or abolish hypoxic response and cytoskeletal organization on hMSCs during the bone regeneration process.
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http://dx.doi.org/10.3390/ijms20071569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480017PMC
March 2019

Adjuvant Biophysical Therapies in Osteosarcoma.

Cancers (Basel) 2019 Mar 12;11(3). Epub 2019 Mar 12.

IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.

Osteosarcoma (OS) is a primary bone sarcoma, manifesting as osteogenesis by malignant cells. Nowadays, patients' quality of life has been improved, however continuing high rates of limb amputation, pulmonary metastasis and drug toxicity, remain unresolved issues. Thus, effective osteosarcoma therapies are still required. Recently, the potentialities of biophysical treatments in osteosarcoma have been evaluated and seem to offer a promising future, thanks in this field as they are less invasive. Several approaches have been investigated such as hyperthermia (HT), high intensity focused ultrasound (HIFU), low intensity pulsed ultrasound (LIPUS) and sono- and photodynamic therapies (SDT, PDT). This review aims to summarize in vitro and in vivo studies and clinical trials employing biophysical stimuli in osteosarcoma treatment. The findings underscore how the technological development of biophysical therapies might represent an adjuvant role and, in some cases, alternative role to the surgery, radio and chemotherapy treatment of OS. Among them, the most promising are HIFU and HT, which are already employed in OS patient treatment, while LIPUS/SDT and PDT seem to be particularly interesting for their low toxicity.
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http://dx.doi.org/10.3390/cancers11030348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468347PMC
March 2019

Long Non Coding RNA H19: A New Player in Hypoxia-Induced Multiple Myeloma Cell Dissemination.

Int J Mol Sci 2019 Feb 13;20(4). Epub 2019 Feb 13.

Department of BioMedicine, Neurosciences and Advanced Diagnostics (Bi.N.D), Via Divisi 83, 90133 Palermo, Italy.

The long non-coding RNA H19 (lncH19) is broadly transcribed in the first stage of development and silenced in most cells of an adult organism; it appears again in several tumors where, through different molecular mediators, promotes cell proliferation, motility and metastases. LncH19 has been associated with hypoxia-inducible factor 1-alpha (HIF-1α) activation and, in some tumors, it has proved to be necessary and required to sustain hypoxic responses. Here we propose to investigate a putative role for the lncH19 in hypoxia induced multiple myeloma (MM) progression. Transcriptional analysis of MM cell lines (RPMI and MM1.S) exposed to normoxia or hypoxia (1% O₂) was done in order to evaluate lncH19 levels under hypoxic stimulation. Then, to investigate the role of lncH19 in hypoxia mediated MM progression, transcriptional, protein and functional assays have been performed on hypoxia stimulated MM cell lines, silenced or not for lncH19. Our data demonstrated that hypoxic stimulation in MM cell lines induced the overexpression of lncH19, which, in turn, is required for the expression of the hypoxia induced genes involved in MM dissemination, such as C-X-C Motif Chemokine Receptor 4 (CXCR4) and Snail. Moreover, adhesion assays demonstrated that lncH19 silencing abrogates the increased adhesion on stromal cells induced by the hypoxic condition. Finally, Western blot analysis indicated that lncH19 silencing impaired HIF1α nuclear translocation. The LncH19, required for the induction of hypoxic responses in MM cells, could represent a new therapeutic target for MM.
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http://dx.doi.org/10.3390/ijms20040801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413127PMC
February 2019

Inhibitory effects of low intensity pulsed ultrasound on osteoclastogenesis induced in vitro by breast cancer cells.

J Exp Clin Cancer Res 2018 Aug 20;37(1):197. Epub 2018 Aug 20.

Laboratory of Preclinical and Surgical Studies, IRCCS Rizzoli Orthopedic Institute, Bologna, Italy.

Background: Bone tissue is one of the main sites for breast metastasis; patients diagnosed with advanced breast cancer mostly develop bone metastasis characterized by severe osteolytic lesions, which heavily influence their life quality. Low Intensity Pulsed Ultrasound (LIPUS) is a form of mechanical energy able to modulate various molecular pathways both in cancer and in health cells. The purpose of the present study was to evaluate for the first time, the ability of LIPUS to modulate osteolytic capability of breast cancer cells.

Methods: Two different approaches were employed: a) Indirect method -conditioned medium obtained by MDA-MB-231 cell line treated or untreated with LIPUS was used to induce osteoclast differentiation of murine macrophage Raw264.7 cell line; and b) Direct method -MDA-MB-231 were co-cultured with Raw264.7 cells and treated or untreated with LIPUS.

Results: LIPUS treatment impaired MDA-MB-231 cell dependentosteoclast differentiation and produced a reduction of osteoclast markers such as Cathepsin K, Matrix Metalloproteinase 9 and Tartrate Resistant Acid Phosphatase, suggesting its role as an effective and safe adjuvant in bone metastasis management.

Conclusion: LIPUS treatment could be a good and safety therapeutic adjuvant in osteolyitic bone metastasis not only for the induction properties of bone regeneration, but also for the reduction of osteolysis.
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http://dx.doi.org/10.1186/s13046-018-0868-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102871PMC
August 2018

Relevance of 3d culture systems to study osteosarcoma environment.

J Exp Clin Cancer Res 2018 Jan 5;37(1). Epub 2018 Jan 5.

IRCCS Rizzoli Orthopedic Institute, Innovative Technologic Platform for Tissue Engineering, Theranostics and Oncology, Via Divisi, 83, 90133, Palermo, Italy.

Osteosarcoma (OS) is the most common primary malignant tumor of bone, which preferentially develops lung metastasis. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for patients with metastatic or recurrent OS remains dramatically poor. Novel therapies are therefore required to slow progression and eradicate the disease. Furthermore, to better understand the cellular and molecular mechanisms responsible for OS onset and progression, the development of novel predictive culture systems resembling the native three-dimensional (3D) tumor microenvironment are mandatory. 'Tumor engineering' approaches radically changed the previous scenario, through the development of advanced and alternative 3D cell culture in vitro models able to tightly mimic the in vivo tumor microenvironment.In this review, we will summarize the state of the art in this novel area, illustrating the different methods and techniques employed to realize 3D OS cell culture models and we report the achieved results, which highlight the efficacy of these models in reproducing the tumor milieu. Although data need to be further validated, the scientific studies reviewed here are certainly promising and give new insights into the clinical practice.
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http://dx.doi.org/10.1186/s13046-017-0663-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756329PMC
January 2018

Circulating biomarkers in osteosarcoma: new translational tools for diagnosis and treatment.

Oncotarget 2017 Nov 3;8(59):100831-100851. Epub 2017 Aug 3.

Rizzoli Orthopedic Institute, Innovative Technology Platforms for Tissue Engineering, Theranostic and Oncology, Palermo, Italy.

Osteosarcoma (OS) is a rare primary malignant bone tumour arising from primitive bone-forming mesenchymal cells, with high incidence in children and young adults, accounting for approximately 60% of all malignant bone tumours. Currently, long-term disease-free survival can be achieved by surgical treatment plus chemotherapy in approximately 60% of patients with localized extremity disease, and in 20-30% of patients with metastatic lung or bone disease. Diagnosis of primary lesions and recurrences is achieved by using radiological investigations and standard tissue biopsy, the latter being costly, painful and hardly repeatable for patients. Therefore, despite some recent advances, novel biomarkers for OS diagnosis, prediction of response to therapy, disease progression and chemoresistance, are urgently needed. Biological fluids such as blood represent a rich source of non-invasive cancer biomarkers, which allow to understand what is really happening inside the tumour, either at diagnosis or during disease progression. In this regard, liquid biopsy potentially represents an alternative and non-invasive method to detect tumour onset, progression and response to therapy. In this review, we will summarize the state of the art in this novel area, illustrating recent studies on OS. Although the data reported in literature seem preliminary, liquid biopsy represents a promising tool with the potential to be rapidly translated in the clinical practice.
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http://dx.doi.org/10.18632/oncotarget.19852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725068PMC
November 2017

Hypoxia-inducible factor 1Α may regulate the commitment of mesenchymal stromal cells toward angio-osteogenesis by mirna-675-5P.

Cytotherapy 2017 12 27;19(12):1412-1425. Epub 2017 Oct 27.

Rizzoli Orthopedic Institute, Bologna, Italy; Rizzoli Orthopedic Institute, Innovative Technological Platforms for Tissue Engineering, Theranostic and Oncology, Palermo, Italy; Rizzoli Orthopedic Institute, Laboratory of Preclinical and Surgical Studies, Bologna, Italy.

Background Aims: During bone formation, angiogenesis and osteogenesis are regulated by hypoxia, which is able to induce blood vessel formation, as well as recruit and differentiate human mesenchymal stromal cells (hMSCs). The molecular mechanisms involved in HIF-1α response and hMSC differentiation during bone formation are still unclear. This study aimed to investigate the synergistic role of hypoxia and hypoxia-mimetic microRNA miR-675-5p in angiogenesis response and osteo-chondroblast commitment of hMSCs.

Methods: By using a suitable in vitro cell model of hMSCs (maintained in hypoxia or normoxia), the role of HIF-1α and miR-675-5p in angiogenesis and osteogenesis coupling was investigated, using fluorescence-activated cell sorting (FACS), gene expression and protein analysis.

Results: Hypoxia induced miR-675-5p expression and a hypoxia-angiogenic response, as demonstrated by increase in vascular endothelial growth factor messenger RNA and protein release. MiR-675-5p overexpression in normoxia promoted the down-regulation of MSC markers and the up-regulation of osteoblast and chondroblast markers, as demonstrated by FACS and protein analysis. Moreover, miR-675-5p depletion in a low-oxygen condition partially abolished the hypoxic response, including angiogenesis, and in particular restored the MSC phenotype, demonstrated by cytofluorimetric analysis. In addition, current preliminary data suggest that the expression of miR-675-5p during hypoxia plays an additive role in sustaining Wnt/β-catenin pathways and the related commitment of hMSCs during bone ossification.

Discussion: MiR-675-5p may trigger complex molecular mechanisms that promote hMSC osteoblastic differentiation through a dual strategy: increasing HIF-1α response and activating Wnt/β-catenin signaling.
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http://dx.doi.org/10.1016/j.jcyt.2017.09.007DOI Listing
December 2017

Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule.

ACS Chem Neurosci 2017 11 22;8(11):2414-2423. Epub 2017 Aug 22.

Department of Chemistry and Biochemistry, Texas Christian University , Fort Worth, Texas 76129, United States.

Metal-ion misregulation and oxidative stress continue to be components of the continually evolving hypothesis describing the molecular origins of Alzheimer's disease. Therefore, these features are viable targets for synthetic chemists to explore through hybridizations of metal-binding ligands and antioxidant units. To date, the metal-binding unit in potential therapeutic small molecules has largely been inspired by clioquinol with the exception of a handful of heterocyclic small molecules and open-chain systems. Heterocyclic small molecules such as cyclen (1,4,7,10-tetraazacyclododecane) have the advantage of straightforward N-based modifications, allowing the addition of functional groups. In this work, we report the synthesis of a triazine bridged system containing two cyclen metal-binding units and an antioxidant coumarin appendage inspired by nature. This new potential therapeutic molecule shows the ability to bind copper in a unique manner compared to other chelates proposed to treat Alzheimer's disease. DPPH and TEAC assays exploring the activity of N-(2-((4,6-di(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)amino)ethyl)-2-oxo-2H-chromene-3-carboxamide (molecule 1) show that the molecule is antioxidant. Cellular studies of molecule 1 indicate a low toxicity (EC = 80 μM) and the ability to protect HT-22 neuronal cells from cell death induced by Aβ + copper(II), thus demonstrating the potential for molecule 1 to serve as a multimodal therapeutic for Alzheimer's disease.
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http://dx.doi.org/10.1021/acschemneuro.7b00184DOI Listing
November 2017

Osteogenic commitment and differentiation of human mesenchymal stem cells by low-intensity pulsed ultrasound stimulation.

J Cell Physiol 2018 Feb 11;233(2):1558-1573. Epub 2017 Jul 11.

Rizzoli Orthopedic Institute, Innovative Technological Platforms for Tissue Engineering, Theranostic and Oncology, Palermo, Italy.

Low-intensity pulsed ultrasound (LIPUS) as an adjuvant therapy in in vitro and in vivo bone engineering has proven to be extremely useful. The present study aimed at investigating the effect of 30 mW/cm LIPUS stimulation on commercially available human mesenchymal stem cells (hMSCs) cultured in basal or osteogenic medium at different experimental time points (7, 14, 21 days). The hypothesis was that LIPUS would improve the osteogenic differentiation of hMSC and guarantying the maintenance of osteogenic committed fraction, as demonstrated by cell vitality and proteomic analysis. LIPUS stimulation (a) regulated the balance between osteoblast commitment and differentiation by specific networks (activations of RhoA/ROCK signaling and upregulation of Ribosome constituent/Protein metabolic process, Glycolysis/Gluconeogenesis, RNA metabolic process/Splicing and Tubulins); (b) allowed the maintenance of a few percentage of osteoblast precursors (21 days CD73+/CD90+: 6%; OCT-3/4+/NANOG+/SOX2+: 10%); (c) induced the activation of osteogenic specific pathways shown by gene expression (early: ALPL, COL1A1, late: RUNX2, BGLAP, MAPK1/6) and related protein release (COL1a1, OPN, OC), in particular in the presence of osteogenic soluble factors able to mimic bone microenvironment. To summarize, LIPUS might be able to improve the osteogenic commitment of hMSCs in vitro, and, at the same time, enhance their osteogenic differentiation.
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http://dx.doi.org/10.1002/jcp.26058DOI Listing
February 2018

Effect of low-intensity pulsed ultrasound on osteogenic human mesenchymal stem cells commitment in a new bone scaffold.

J Appl Biomater Funct Mater 2017 Jul 27;15(3):e215-e222. Epub 2017 Jul 27.

Rizzoli Orthopedic Institute, Innovative Technological Platforms for Tissue Engineering, Theranostic and Oncology, Palermo - Italy.

Purpose: Bone tissue engineering is helpful in finding alternatives to overcome surgery limitations. Bone growth and repair are under the control of biochemical and mechanical signals; therefore, in recent years several approaches to improve bone regeneration have been evaluated. Osteo-inductive biomaterials, stem cells, specific growth factors and biophysical stimuli are among those. The aim of the present study was to evaluate if low-intensity pulsed ultrasound stimulation (LIPUS) treatment would improve the colonization of an MgHA/Coll hybrid composite scaffold by human mesenchymal stem cells (hMSCs) and their osteogenic differentiation. LIPUS stimulation was applied to hMSCs cultured on MgHA/Coll hybrid composite scaffold in osteogenic medium, mimicking the microenvironment of a bone fracture.

Methods: hMSCs were seeded on MgHA/Coll hybrid composite scaffold in an osteo-inductive medium and exposed to LIPUS treatment for 20 min/day for different experimental times (7 days, 14 days). The investigation was focused on (i) the improvement of hMSCs to colonize the MgHA/Coll hybrid composite scaffold by LIPUS, in terms of cell viability and ultrastructural analysis; (ii) the activation of MAPK/ERK, osteogenic (ALPL,COL1A1,BGLAP,SPP1) and angiogenetic (VEGF, IL8) pathways, through gene expression and protein release analysis, after LIPUS stimuli.

Results: LIPUS exposure improved MgHA/Coll hybrid composite scaffold colonization and induced in vitro osteogenic differentiation of hMSCs seeded on the scaffold.

Conclusions: This work shows that the combined use of new biomimetic osteo-inductive composite and LIPUS treatment could be a useful therapeutic approach in order to accelerate bone regeneration pathways.
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http://dx.doi.org/10.5301/jabfm.5000342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379883PMC
July 2017

Formation of Dendrimer Nanoassemblies by Oligomerization-Induced Liquid-Liquid Phase Separation.

Langmuir 2017 06 22;33(22):5482-5490. Epub 2017 May 22.

Department of Chemistry & Biochemistry, Texas Christian University , Fort Worth, Texas 76129, United States.

Dendrimers are hyperbranched macromolecules with applications in host-guest chemistry, self-assembly, nanocatalysis, and nanomedicine. We show that dendrimer-based globular nanoparticles are formed by using dendrimer oligomerization to isothermally induce liquid-liquid phase separation (LLPS). We first determined that LLPS of aqueous mixtures of the fourth-generation amino-functionalized poly(amido amine) dendrimer is observed by lowering temperature in the presence of sodium sulfate. In relation to LLPS, we experimentally characterized the effect of salt and dendrimer concentrations on the LLPS temperature and salt-dendrimer isothermal partitioning. Our results were theoretically examined using a two-parameter thermodynamic model. We then showed that the addition of a small amount of glutaraldehyde, which leads to the formation of soluble dendrimer oligomers by chemical cross-linking, increases the LLPS temperature. This implies that a dendrimer aqueous mixture, which is initially homogeneous at room temperature and exhibits LLPS only at relatively low temperatures, can exhibit LLPS at room temperature due to dendrimer oligomerization. The high dendrimer concentration inside the nanodroplets, produced from LLPS, accelerates dendrimer cross-linking, thereby yielding stable globular nanoparticles. These nanomaterials retain the host-guest properties of the initial dendrimers, indicating potential applications as nanocatalysts, extracting agents and drug carriers. Our work provides the basis for a new approach for obtaining dendrimer-based nanoassemblies by employing low-generation dendrimers as building blocks.
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http://dx.doi.org/10.1021/acs.langmuir.7b00911DOI Listing
June 2017

Data on the effects of low iron diet on serum lipid profile in HCV transgenic mouse model.

Data Brief 2017 Jun 18;12:22-25. Epub 2017 Mar 18.

Dipartimento di Biotecnologie Cellulari ed Ematologia, Sapienza University of Rome, Rome 00185, Italy.

Here, we presented new original data on the effects of iron depletion on the circulating lipid profile in B6HCV mice, a murine model of HCV-related dyslipidemia. Male adult B6HCV mice were subjected to non-invasive iron depletion by low iron diet. Serum iron concentration was assessed for evaluating the effects of the dietary iron depletion. Concentrations of circulating triglycerides, total cholesterol, Low Density Lipoproteins (LDLs), High Density Lipoproteins (HDLs) were analyzed and reported by using stacked line charts. The present data indicated that low serum iron concentration is associated to i) lower serum triglycerides concentrations and ii) increased circulating LDLs. The presented original data have not been published elsewhere.
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http://dx.doi.org/10.1016/j.dib.2017.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367794PMC
June 2017

Prevalence and Determinants of Bullying Among Health Care Workers in Portugal.

Workplace Health Saf 2017 May 6;65(5):188-196. Epub 2017 Jan 6.

3 Faculty of Education and Psychology, Catholic University of Portugal, Porto, Portugal.

Bullying is defined as systematic exposure to humiliation as well as hostile and violent behaviors against one or more individuals. These behaviors are a serious, growing problem, which affects a significant proportion of health care professionals. To support the hospital's risk management policy, a cross-sectional study was undertaken to determine the prevalence of bullying in this institution and identify the determinants of bullying. Bullying was measured using the Negative Acts Questionnaire-Revised, Portuguese version (NAQ-R), a self-administered tool. The questionnaire was made available in digital format on the hospital's internal network (Intranet) and in hard copy; questionnaires were returned via nonidentified internal mail addressed to the occupational health unit or deposited in suggestion boxes located throughout the hospital. Multiple questionnaire delivery methods guaranteed data anonymity and confidentiality. The prevalence of bullying in this hospital was 8% (95% confidence interval [CI] = [6.2, 10.2]). Reported bullying was predominantly vertical and more frequently occurring among nurses, clerical staff, and health care assistants (12.5%, 7.6%, 6.4%, respectively; p = .005). After adjusting for gender, age, occupation, type of contract, and work schedule, only type of contract was significantly associated with bullying in the workplace; the risk of bullying was twice as high among government employees compared to workers with indefinite duration employment contracts ( p = .038). This study identified a high prevalence of bullying among health professionals; hence a program to prevent and control this phenomenon was implemented in this institution.
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http://dx.doi.org/10.1177/2165079916666545DOI Listing
May 2017

MiR-675-5p supports hypoxia induced epithelial to mesenchymal transition in colon cancer cells.

Oncotarget 2017 Apr;8(15):24292-24302

Dipartimento di Biotecnologie Cellulari ed Ematologia, Sapienza University of Rome, Rome, Italy.

The survival rates in colon cancer patients are inversely proportional to the number of lymph node metastases. The hypoxia-induced Epithelial to Mesenchymal Transition (EMT), driven by HIF1α, is known to be involved in cancer progression and metastasis. Recently, we have reported that miR-675-5p promotes glioma growth by stabilizing HIF1α; here, by use of the syngeneic cell lines we investigated the role of the miR-675-5p in colon cancer metastasis.Our results show that miR-675-5p, over expressed in metastatic colon cancer cells, participates to tumour progression by regulating HIF1α induced EMT. MiR-675-5p increases Snail transcription by a dual strategy: i) stabilizing the activity of the transcription factor HIF1α and ii) and inhibiting Snail's repressor DDB2 (Damage specific DNA Binding protein 2).Moreover, transcriptional analyses on specimens from colon cancer patients confirmed, in vivo, the correlation between miR-675-5p over-expression and metastasis, thus identifying miR-675-5p as a new marker for colon cancer progression and therefore a putative target for therapeutic strategies.
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http://dx.doi.org/10.18632/oncotarget.14464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421847PMC
April 2017

Vitamin D Level Between Calcium-Phosphorus Homeostasis and Immune System: New Perspective in Osteoporosis.

Curr Osteoporos Rep 2016 Oct 13. Epub 2016 Oct 13.

Innovative Technology Platforms for Tissue Engineering, Theranostics and Oncology, Rizzoli Orthopaedic Institute, Via Divisi, 83, 90100, Palermo, Italy.

Vitamin D is a key molecule in calcium and phosphate homeostasis; however, increasing evidence has recently shown that it also plays a crucial role in the immune system, both innate and adaptive. A deregulation of vitamin D levels, due also to mutations and polymorphisms in the genes of the vitamin D pathway, determines severe alterations in the homeostasis of the organism, resulting in a higher risk of onset of some diseases, including osteoporosis. This review gives an overview of the influence of vitamin D levels on the pathogenesis of osteoporosis, between bone homeostasis and immune system.
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http://dx.doi.org/10.1007/s11914-016-0331-2DOI Listing
October 2016

MiR675-5p Acts on HIF-1α to Sustain Hypoxic Responses: A New Therapeutic Strategy for Glioma.

Theranostics 2016 8;6(8):1105-18. Epub 2016 May 8.

6. Dipartimento di Biotecnologie Cellulari ed Ematologia, Sapienza University of Rome, Rome 00185, Italy;

Hypoxia is a common feature in solid tumours. In glioma, it is considered the major driving force for tumour angiogenesis and correlates with enhanced resistance to conventional therapies, increased invasiveness and a poor prognosis for patients. Here we describe, for the first time, that miR675-5p, embedded in hypoxia-induced long non-coding RNA H19, plays a mandatory role in establishing a hypoxic response and in promoting hypoxia-mediated angiogenesis. We demonstrated, in vitro and in vivo, that miR675-5p over expression in normoxia is sufficient to induce a hypoxic moreover, miR675-5p depletion in low oxygen conditions, drastically abolishes hypoxic responses including angiogenesis. In addition, our data indicate an interaction of miR675-5p, HIF-1α mRNA and the RNA Binding Protein HuR in hypoxia-induced responses. We suggest the modulation of miR675-5p as a new therapeutic option to promote or abolish hypoxia induced angiogenesis.
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http://dx.doi.org/10.7150/thno.14700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893639PMC
October 2017

Thermoregulated Coacervation, Metal-Encapsulation and Nanoparticle Synthesis in Novel Triazine Dendrimers.

Molecules 2016 May 11;21(5). Epub 2016 May 11.

Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, TX 76129, USA.

The synthesis and solubility behaviors of four generation five (G5) triazine dendrimers are studied. While the underivatized cationic dendrimer is soluble in water, the acetylated and propanoylated derivatives undergo coacervation in water upon increasing temperature. Occurring around room temperature, this behavior is related to a liquid-liquid phase transition with a lower critical solution temperature (LCST) and is explained by differences in composition, notably, the hydrophobic nature of the terminal groups. Interestingly, the water solubility of the acetylated dendrimer is affected by the addition of selected metal ions. Titrating solutions of acetylated dendrimer at temperatures below the LCST with gold or palladium ions promoted precipitation, but platinum, iridium, and copper did not. Gold nanoparticles having diameters of 2.5 ± 0.8 nm can be obtained from solutions of the acetylated dendrimer at concentrations of gold less than that required to induce precipitation by treating the solution with sodium borohydride.
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http://dx.doi.org/10.3390/molecules21050599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273988PMC
May 2016

Unusual liquid-liquid phase transition in aqueous mixtures of a well-known dendrimer.

Phys Chem Chem Phys 2015 Nov;17(43):28818-29

Department of Chemistry, Texas Christian University, Fort Worth, Texas 76129, USA.

Liquid-liquid phase separation (LLPS) has been extensively investigated for polymer and protein solutions due to its importance in mixture thermodynamics, separation science and self-assembly processes. However, to date, no experimental studies have been reported on LLPS of dendrimer solutions. Here, it is shown that LLPS of aqueous solutions containing a hydroxyl-functionalized poly(amido amine) dendrimer of fourth generation is induced in the presence of sodium sulfate. Both the LLPS temperature and salt-dendrimer partitioning between the two coexisting phases at constant temperature were measured. Interestingly, our experiments show that LLPS switches from being induced by cooling to being induced by heating as the salt concentration increases. The two coexisting phases also show opposite temperature response. Thus, this phase transition exhibits a simultaneous lower and upper critical solution temperature-type behavior. Dynamic light-scattering and dye-binding experiments indicate that no appreciable conformational change occurs as the salt concentration increases. To explain the observed phase behavior, a thermodynamic model based on two parameters was developed. The first parameter, which describes dendrimer-dendrimer interaction energy, was determined by isothermal titration calorimetry. The second parameter describes the salt salting-out strength. By varying the salting-out parameter, it is shown that the model achieves agreement not only with the location of the experimental binodal at 25 °C but also with the slope of this curve around the critical point. The proposed model also predicts that the unusual temperature behavior of this phase transition can be described as the net result of two thermodynamic factors with opposite temperature responses: salt thermodynamic non-ideality and salting-out strength.
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http://dx.doi.org/10.1039/c5cp04642dDOI Listing
November 2015

CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA.

Mol Cancer 2015 Aug 14;14:155. Epub 2015 Aug 14.

Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Via Divisi 83-90133, Palermo, Italy.

Background: CD90+ liver cancer cells have been described as cancer stem-cell-like (CSC), displaying aggressive and metastatic phenotype. Using two different in vitro models, already described as CD90+ liver cancer stem cells, our aim was to study their interaction with endothelial cells mediated by the release of exosomes.

Methods: Exosomes were isolated and characterized from both liver CD90+ cells and hepatoma cell lines. Endothelial cells were treated with exosomes, as well as transfected with a plasmid containing the full length sequence of the long non-coding RNA (lncRNA) H19. Molecular and functional analyses were done to characterize the endothelial phenotype after treatments.

Results: Exosomes released by CD90+ cancer cells, but not by parental hepatoma cells, modulated endothelial cells, promoting angiogenic phenotype and cell-to-cell adhesion. LncRNA profiling revealed that CD90+ cells were enriched in lncRNA H19, and released this through exosomes. Experiments of gain and loss of function of H19 showed that this LncRNA plays an important role in the exosome-mediated phenotype of endothelial cells.

Conclusions: Our data indicate a new exosome-mediated mechanism by which CSC-like CD90+ cells could influence their tumor microenvironment by promoting angiogenesis. Moreover, we suggest the lncRNA H19 as a putative therapeutic target in hepatocellular carcinoma.
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http://dx.doi.org/10.1186/s12943-015-0426-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536801PMC
August 2015

Human cord blood-derived hemogenic endothelium generates mast cells.

Blood Cells Mol Dis 2015 Feb 15;54(2):195-7. Epub 2014 Nov 15.

Department of Hmatology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

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http://dx.doi.org/10.1016/j.bcmd.2014.11.002DOI Listing
February 2015

Bimodal-hybrid heterocyclic amine targeting oxidative pathways and copper mis-regulation in Alzheimer's disease.

Metallomics 2014 Nov;6(11):2072-82

Department of Chemistry, Texas Christian University, 2800 S. University, Fort Worth, USA.

Oxidative stress resulting from metal-ion misregulation plays a role in the development of Alzheimer's disease (AD). This process includes the production of tissue-damaging reactive oxygen species and amyloid aggregates. Herein we describe the synthesis, characterization and protective capacity of the small molecule, lipoic cyclen, which has been designed to target molecular features of AD. This construct utilizes the biologically compatible and naturally occurring lipoic acid as a foundation for engendering low cellular toxicity in multiple cell lines, radical scavenging capacity, tuning the metal affinity of the parent cyclen, and results in an unexpected affinity for amyloid without inducing aggregation. The hybrid construct thereby shows protection against cell death induced by amyloid aggregates and copper ions. These results provide evidence for the rational design methods used to produce this fused molecule as a potential strategy for the development of lead compounds for the treatment of neurodegenerative disorders.
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http://dx.doi.org/10.1039/c4mt00161cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206570PMC
November 2014