15,502 research outputs found
New chiral clofibric acid analogues as ligands of Peroxisome Proliferator-Activated Receptor (PPAR) alpha and gamma
No full textEffects of novel sintetic peroxisome proliferator-activation receptor (PPARs) agonist on neuronal differentiation in the human neuroblastoma SH-SY5Y cell line.
No full textEffects of novel sintetic peroxisome proliferator-activation receptor (PPARs) agonist on neuronal differentiation in the human neuroblastoma SH-SY5Y cell line
MALLAMACI R1, LAGHEZZA A3,LOIODICE F3, VITIELLO F2, BUTTIGLIONE M2
1Dip.Pharmaceutical Biology, Faculty of Pharmacy, University of Bari
2Dip.Biomedical Sciences and Human Oncology, Faculty of Medicine, University of Bari
3Dip. Pharmaceutical Chemistry, Faculty of Pharmacy, University of Bari
BACKGROUND: PPARs are a subfamily of the nuclear hormone receptor that heterodimerizes with the retinoid X receptor to act as a transcriptional regulator. Recently it has been shown that the activation of PPARγ isoform promotes neuronal differentiation.
AIM: In this study we have investigated the capability of synthetic compounds endowed with different activity profile on PPARα/γ subtypes to induce neuronal differentiation and neurite outgrowth. The experiments were carried out on cells of the human neuroblastoma SH-SY5Y line. Retinoic acid (RA) was used as a positive control for neurite outgrowth.
METHODS: SH-SY5Y cultures were maintained in DMEM supplemented with 10% FCS. 10μM RA, 0,5 to 25μM PPAR agonist was added to the culture media in the experimental cultures. Cell viability was tested using the MTT assay. Changes in the expression and re-organization of specific markers involved in neuronal differentiation were investigated using immunofluorescence.
RESULTS: Synthetic PPAR agonists promote cell differentiation and the outgrowth of cell processes in a concentration-dependent manner. The maximal effect was obtained at a concentration of 25μM. At this concentration we obtained a significant increase of the expression of neurofilament-200 (NF-H) and Gap-43; this agrees with a hypothesis of cell differentiation induced by these molecules. CONCLUSION: Our results suggest that sintetic PPAR agonist promotes neuronal differentiation and neurite outgrowth in SH-SY5Y human neuroblastoma cells. Further work on this subject is underway in our laboratories
Declaration of Intention for Antonio Franchihtti
No full textDeclaration of Intention to become a citizen of the United States, as filled out and signed by Antonio Franchitti. Applicant lists himself as a 47 year old farmer residing in Hammonton, New Jersey, born in Campombosso, Italy on 18 April 1870, who sailed on the US bound vessel Britania. Declaration submitted and sworn April 21, 1917
The role of educative thought in the life and work of Antonio Gramsci
No full textMany philosophers have propounded a vision of an improved society, what distinguishes Antonio Gramsci is his continuous effort to make it happen by understanding the process in order to put into practice. Gramsci's conviction about the importance of educative development came from both theory and experience. While there has been considerable examination of Gramsci's work in relation to the Prison Notebooks, this study will seek to address a lacuna in Gramsci scholarship. Using Gramsci's philological method, I analyse Gramsci's pre-prison activity; his pre-prison articles and letters, which, together with his letters from prison, formed part of his educative mission. This educative process was necessary, in order to construct a new party which would develop a collective will, collaboratively, with the masses.In this study therefore, I explore the contexts and formative experiences of the first part of his life together with the intellectual sources from which Gramsci developed his later theories, making central hitherto underemphasised connections between them which informed his writing and ideas. I intend to illustrate that Gramsci's underlying purpose in his writing, and political activity, was not only practical, on how to create a new socialist ruling class, but also educative in forming the mindset and values of his comrades. So that in addition to outlining his vision of a new order, he implicitly guided or explicitly explained the processes by which the necessary changes in social relations and moral climate could be made in order to achieve it. Each person had to engage with the values of the new order so that each could contribute to the construction of a new robust state. It was essential to build a hegemony at the most profound level, one which was dependent on collective understandings and a collective will
Abstract P6-16-02: Treatment of skeletal metastatic breast cancer with bone seeking matrix metalloproteinase inhibitors
No full textBackground. Breast to bone metastasis is a common event during breast cancer progression. The resultant lesions are painful and currently, despite medical advances, are incurable. The progression of bone metastatic breast cancer is critically dependent on interactions with the surrounding microenvironment. Therefore, identifying the underpinning molecular mechanisms is vital for the development of new therapies.
Rationale. Gene expression analysis and validation in human and murine specimens of bone metastases revealed matrix metalloproteinases, such as MMP-2, are highly expressed in the bone metastatic microenvironment. Genetic ablation of MMP-2 demonstrated the importance of this MMP in driving the growth of the osteolytic bone metastatic breast cancer by regulating the bioavailability of transforming growth factor β (TGFβ). These data support the rationale for the development of a highly specific MMP-2 inhibitor for the eradication of active bone metastatic breast cancer.
Methods. Given that previous broad-spectrum MMP inhibitor (MMPI) trials were unsuccessful due to dose limiting systemic side effects, we utilized a novel chemical approach to synthesize bone seeking MMP inhibitors (BMMPIs) on a bisphosphonic backbone, with specificity for MMP-2 in the nanomolar range (IC50=140 nM). In vitro, we tested the effect of BMMPIs at varying doses (1nM-100μM) on the viability of the major cellular components of the cancer-bone microenvironment, namely breast cancer cells (PyMT, 4T1), osteoblasts (MC3T3) and osteoclasts (primary monocytes and RAW 264.7). In vivo, mice were intratibially inoculated with either luciferase expressing 4T1 or PyMT (1x105) cells. Mice (n=10/group) then received vehicle, zoledronate (1 mg/kg) or BMMPIs (1 mg/kg). Tumor growth was determined via luminescence quantitation. Cancer induced bone disease was measured ex vivo by μCT, Xray and histomorphometry. MMP activity in vivo and ex vivo was determined via specific activatable MMP probes.
Results. BMMPIs significantly impacted the viability of breast cancer cells and osteoclasts in vitro (p<0.05) compared to control. In vivo BMMPIs significantly reduced the growth of bone metastatic breast cancer compared to control and the standard of care bisphosphonate, zoledronate. MMP activity was also lower in the BMMPI treated groups (using tumor burden to normalize values). μCT/Xray/Histomorphometry analysis also illustrated the significant beneficial effects of the BMMPIs in reducing the size of osteolytic lesions (up to 80% by μCT; p<0.05).
Conclusions. MMP-2 specific BMMPIs prevent bone metastatic breast cancer growth by impacting cancer cell viability and cancer induced osteolysis. Given that bisphosphonates are well tolerated in the clinical setting, we predict that BMMPIs could be translated to the clinical setting for the treatment and eradication of bone metastatic breast cancer
Abstract 398: Specific skeletal targeting of MMP-2 inhibitors for the treatment of bone metastatic breast cancer
No full textBackground. Bone metastatic breast cancer promotes extensive bone destruction/osteolysis and is currently incurable. Progression of the disease is critically dependent on cancer-bone interaction. Defining the molecular mechanisms underlying this communication can lead to the identification of new therapeutic targets that will eradicate the disease.
Rationale. Gene expression analysis and validation in human and murine specimens of bone metastases revealed that matrix metalloproteinases (MMPs) such as MMP-2 are highly expressed in the bone metastatic microenvironment. Genetic ablation of MMP-2 highlighted the importance of this MMP in driving the growth of the osteolytic breast cancer lesions. We subsequently found that MMP-2 regulation of transforming growth factor β (TGF β) bioavailability was a major mechanism through which MMP-2 mediated this effect. These data support the rationale for the development of selective MMP inhibitors and imply that MMP-2 inhibition would be a successful strategy for the eradication of active bone metastatic breast cancer.
Methods. To address systemic dose limiting side effects noted in previous broad spectrum MMP inhibitor trials, we utilized a novel chemical approach to generate bone-targeting, highly selective MMP-2 inhibitors grafted onto a bisphosphonic backbone. In vitro, we tested the effect of BMMPIs at varying doses (1nM-100μM) on the viability of the major cellular components of the cancer-bone microenvironment, namely breast cancer cells (PyMT, 4T1), osteoblasts (MC3T3) and osteoclasts (primary monocytes and RAW 264.7). In vivo, mice were inoculated with either luciferase expressing 4T1 or PyMT (100,000) cells. Mice (n = 10/group) then received vehicle, zoledronate (1 mg/kg) or BMMPIs (1 mg/kg). Tumor growth was determined via luminescence quantitation. Cancer induced bone disease was measured ex vivo by μCT, Xray and histomorphometry. MMP activity in vivo and ex vivo was determined via an activatable MMP probe.
Results. BMMPIs significantly impacted the viability of breast cancer cells and osteoclasts in vitro (p<0.05) compared to control. In vivo BMMPIs significantly reduced the growth of bone metastatic breast cancer compared to control and the standard of care bisphosphonate, zoledronate. MMP activity was also lower in the BMMPI treated groups (using tumor burden to normalize values). μCT/Xray/Histomorphometry analysis also illustrated the significant beneficial effects of the BMMPIs in reducing the size of osteolytic lesions (up to 80% by μCT; p<0.05).
Conclusions. MMP-2 specific BMMPIs prevent bone metastatic breast cancer growth by impacting cancer cell viability and cancer induced osteolysis. Given that bisphosphonates are well tolerated in the clinical setting, we predict that BMMPIs could be translated to the clinical setting for the treatment and eradication of bone metastatic breast cancer
New Approaches to Cancer Therapy: Combining Fatty Acid Amide Hydrolase (FAAH) Inhibition with Peroxisome Proliferator-Activated Receptors (PPARs) Activation
No full textOver the course of the past decade, peroxisome proliferator-activated receptors (PPARs) have been identified as part of the cannabinoid signaling system: both phytocannabinoids and endocannabinoids are capable of binding and activating these nuclear receptors. Fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and other N-acylethanolamines. These substances have been shown to have numerous anticancer effects, and indeed the inhibition of FAAH has multiple beneficial effects that are mediated by PPARα subtype and by PPARγ subtype, especially antiproliferation and activation of apoptosis. The substrates of FAAH are also PPAR agonists, which explains the PPAR-mediated effects of FAAH inhibitors. Much like cannabinoid ligands and FAAH inhibitors, PPARγ agonists show antiproliferative effects on cancer cells, suggesting that additive or synergistic effects may be achieved through the positive modulation of both signaling systems. In this Miniperspective, we discuss the development of novel FAAH inhibitors able to directly act as PPAR agonists and their promising utilization as leads for the discovery of highly effective anticancer compounds
Abstract 4858: A novel strategy for the selective and tissue specific inhibition of MMPs in active breast cancer to bone metastases
No full text
Probing the S1’ Site for the Identification of Non-Zinc- Binding MMP-2 Inhibitors
No full textMatrix metalloproteinases (MMPs) are zinc-dependent enzymes
involved in several pathological states. Among them, MMP-2 is
a relevant therapeutic target because of its role in cancer development
and progression. Many MMP inhibitors (MMPIs)
have been discovered over the last 30 years, and the majority
of them contain a functional group that binds the zinc ion
(zinc-binding group; ZBG). Unfortunately, no MMPIs have
reached the market yet, owing to toxic effects due to unselective
interactions of the ZBG. The new generation of MMPIs
that do not bind the zinc ion could overcome problems of selectivity
and toxicity, but have so far been developed only for MMP-8, -12, and -13. In this work, a virtual screening protocol
was established by combining ligand- and structure-based
methods to identify non-zinc-binding MMP-2 inhibitors using
a new-generation MMP-8 inhibitor as a probe to find unexplored
interactions in the MMP-2 S1’ site. The screening allowed
the identification of micromolar MMP-2 inhibitors that
putatively avoid binding the zinc ion, as demonstrated by
docking calculations. The LIA model, built to correlate predicted
and experimental binding energies of the identified nonzinc-
binding MMP-2 hits, underpins the reliability of the predicted
docking poses
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