Genetic cancer drug targets


Atherosclerosis is considered as the end result of dyslipidemia and a strong inflammatory process. Extensive evidence revealed that inflammation is a key contributor to all stages of this disease, from the initial lesion to the ruptured plaque. However, there are many instances genetic cancer drug targets which inflammatory reactions induced by genetic cancer drug targets antigens that stimulate immune cells induce atherosclerotic plaque formation in the absence of systemic dyslipidemia.

Moreover recent clinical studies indicate thatthe vascular inflammation might be a factor that promotes atherosclerosis and the formation of aneurysms. The mechanism of vascular inflammation and the reason for accelerated atherosclerosis in patients with inflammatory rheumatic disease remain unclear. Although it was reported that cytokines and chemokines participate in this process, their mechanism of action and their effect on the cellular constituents of the atheroma is not very well known.

Resistin is a It is a cytokine with an established function in mice as a molecular link between obesity and diabetes and with an unclear function in humans, where it appears as a pro-inflammatory molecule associated with both acute and chronic inflammation neutrophils and monocytes are genetic cancer drug targets sources of resistin. In the atherosclerotic lesions increased resistin presence was associated with macrophages and very recent data suggested that resistin, when present at high levels locally, in the arterial vessel wall significantly contributes to an enhanced accumulation genetic cancer drug targets macrophages by increasing monocytes chemotaxis and survival,bymechanisms that need to be further clarified.

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The resistin receptor is genetic cancer drug targets known in vascular cells. Recently, Toll-like receptor 4 TLR 4 was proposed to be a receptor for the proinflammatory effects of resistin in monocytes and Gi proteins signaling suggested to be involved in resistin chemotactic effects in human. Fractalkine CX3CL1 is an atypical chemokine that functions as chemoattractant or as adhesion molecule, facilitating monocyte and T cell transmigration in atherosclerotic lesion prone areas.

Recently, fractalkine was even proposed as an early endothelial marker of atherosclerosis by a complex study of global gene expression profile from human arterial endothelial cells in different stages of atherosclerosis.

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The presence of fractalkine and its cognate receptor was demonstrated in human coronary artery atherosclerotic plaque, genetic cancer drug targets the sub-endothelium and not in normal artery, but the role of fractalkine presence in this location was not well characterized. Thus we questioned whether the interaction between resistin and fractalkine, enhances the inflammatory process and if so, one could find ways to reduce the process.

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Our recent genetic cancer drug targets fractalkine Fk as a new molecular link between resistin and inflammation and showedthat resistin increases monocyte adhesion by mechanisms involving endothelial cell adhesion molecules P-selectin and Fk. The use of nanotechnology in cardiovascular disease treatment may have unprecedented benefits in preventing atherosclerosis progression.

The concept of targeted drug delivery using nanoparticles NP is an appealing therapeutic strategy because of its advantages such as the ability to target specific and restricted locations genetic cancer drug targets the body, to deliver effective concentration of drugs to the diseased sites and to reduce the drug concentrations at non-target sites resulting in fewer side effects. Working hypothesis. In inflammation, resistin Rthat is present in high concentration in the inflamed vessel wall, activates endothelial cells EC and intimal smooth muscle cells SMC determining enhanced monocytes M infiltration by specific mechanisms involving up-regulation of fraktalkine, MCP-1, TLR4 and Gi protein activation Figure, panel A.

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Subsequently, within the intima, modulation of monocytes phenotype, their proliferation and differentiation in genetic cancer drug targets macrophages and the cross-talk between the monocyte-derived macrophages and SMC induces changes in the signaling pathways, augments genetic cancer drug targets of pro-atherogenic molecules cancer hodgkin s lymphoma survival rate accelerate inflammation-induced genetic cancer drug targets formation Figure, panel B.

The relevant molecules found to be instrumental in the EC and M activation could be used as targets for a novel anti-inflammatory nanotherapy employing drugs-carrying nanoparticles NP.

This hypothesis based on our preliminary data will be tested by the objectives of this proposal. Objectives: Objective 1: To explore the role of subendothelial resistin on monocytes transmigration. Objective 2: To analyze the resistin and fractalkine-induced monocytes and smooth muscle cells phenotype modulation and the molecular mechanisms involved in macrophage-SMC cross-talk.

Objective 3: To develop new targeted therapeutic strategies to reduce vascular wall inflammation based on nanotechnology. Collectively, the molecular mechanism revealed by our study will help to get further insight into the complexity of the signaling mechanisms and gene regulation of some key molecules involved and to develop new targeted therapeutic strategies based on nanotechnology to reduce vascular wall inflammation.

Our project will identify novel drug targets and would provide important knowledge for developing strategies for better management of vascular disease. The data will be applicable genetic cancer drug targets the numerous diseases in which inflammation is involved, genetic cancer drug targets as such as atherosclerosis, chronic rheumatic diseases, diabetes, cancer and neurodegenerative diseases. Impact and relevance. However the results will go well beyond the CVD because inflammation is implicated in numerous pathologies such as diabetes, cancer, neurodegenerative diseases and chronic rheumatic diseases.

Thus the results will have an impact in all these pathologies. The molecular mechanism revealed will help to get further insight into the complexity of the signaling mechanisms and gene regulation of some key molecules involved and to develop new targeted therapeutic strategies based on nanotechnology to reduce vascular wall inflammation.

The outcome of this project is highly relevant for biomedical science genetic cancer drug targets it uses cellular and molecular biology tools to help to better understand clinical data, and by our ongoing collaboration with rheumatologists and cardiologists we will correlate the obtained data with clinical data facilitating a continuous two way transfer from bench to bedside.

Altogether, the continuous close collaboration we have with a rheumatology and a cardiology clinic will increase the professional competency of researchers, clinicians, medical residents, masters and PhD students and by dissemination of the results the visibility of biomedical Romanian science. Project implementation Stage  1 During the period between October and Decemberthe project implementation was performed by executing Task 1.

In the human atherosclerotic plaque resistin accumulates within the subendothelial space and enhances leukocyte transmigration by mechanisms that are not well known. Receptors for resistin have not been identified in vascular cells. The aim of our study is to uncover the signaling pathways involved in the production of the chemokines fractalkine and MCP-1 by high subendothelial resistin.

Observations: Human endothelial cells HEC were cultured on membrane inserts in two compartment systems and resistin was added in the lower chamber for 6,18 and 24 hours. Our data will help to develop new targeted anti-inflammatory therapy employing drugs-carrying nano-particles.

Stage  2 Project implementation during  January to  December was carried out by performing Stage  2: Signaling pathways involved in up-regulating fractalkine and MCP-1 expression by subendothelial resistin in vascular cells. In the period mentioned above, tasks of the first objective To explore the role of subendothelial resistin on monocytes transmigration  were performed: Task 1.

Revealing of new intracellular signaling pathways involved in chemokines Fk, MCP-1 expression in response to high resistin in genetic cancer drug targets.

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Task 1. Resistin effect on TLR4 expression. The abstract was selected for the Moderated Poster Session assigned as M37 and the no. Aim: It has been reported that within the human plaque, resistin secreted by the recruited leukocytes accumulates within the subendothelial space. We hypothesize that in this location resistin activates endothelial cells EC and smooth muscle cells SMC and enhance monocyte transmigration, by mechanisms that we plan to uncover.

Methods: We have used an in vitro system, a co-culture in which SMC were grown on the lower chamber and the EC were grown on membrane insert upper chamber. Resistin was genetic cancer drug targets luminal or subendothelial for 2 and 24h and calcein-labeled human monocytes isolated with CD14 microbeads were added on the EC layer. The transmigrated monocytes were counted under the microscope or by measure of calcein fluorescence.

The role of TLR4 and Gi proteins activation in resistin-induced monocyte transmigration was evaluated by incubation with specific antibodies or inhibitors for these pathways.

Results: Our data showed that: i subendothelial resistin induced enhanced monocyte transmigration compared to luminal resistin and ii subendothelial resistin induced an increased monocyte transmigration in co-cultured EC-SMC compared to monocyte transmigration through only the EC monolayer.

Conclusion: Resistin enhances monocyte transmigration by mechanisms involving fractalkine and MCP1 genetic cancer drug targets the activation of TLR4 and Gi proteins signaling. Investigation of the molecular mechanisms instrumental in resistin induced monocyte transmigration may be important for using the involved molecules as targets for novel anti-inflammatory nanotherapy employing drugs-carrying nanoparticles. Investigation of resistin role on TLR4 expression on the cell surface 1.

Cell Tissue Res. Epub Oct Abstract: In the atherosclerotic genetic cancer drug targets, smooth muscle cells SMC acquire an inflammatory phenotype. Resistin and fractalkine CX3CL1 are found genetic cancer drug targets human atheroma and not in normal arteries. The CX3CL1 induced by resistin exhibited a chemotactic effect on monocyte transmigration.

The data reveal new mechanisms by which resistin promotes the inflammatory phenotype of SMC. Investigationof the resistin-dependent signaling pathways involved in regulation of Fk expression in SMC 1. In silico analysis of human fractalkine promoter 1.

Cloning the human fractalkine promoter 1. Functional activity evaluation of fractalkine promoter in vascular SMC 1.

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Physical interactions of transcription factors in fractalkine promoter — canonic and non-canonic protein-DNA interactions Task 1.

Investigation the role of oxidative stress in resistin-induced Fk expression in SMC 1. In order to uncover transcriptional regulation of Fk expression, in this study, we characterized the promoter of the human Fk gene and investigated genetic cancer drug targets role of various transcription factors in its papiloame pe vagin in human aortic SMC.

Materials and Methods. The Fk promoter was cloned in the pGL3 basic reporter vector. Identification of specific transcription factors that are involved in Fk regulation was determined by in silico analysis and chromatin immunoprecipitation ChIP methods.

Results and Discussions. Task 2 conclusion: High concentration of resistin activates human vascular cells endothelial and smooth muscle cells by specific mechanisms involving up-regulation of FK and MCP-1 expression, increasing oxidative stress and activation of Gi proteins and TLR4 signaling pathways.

All these mechanisms could be involved in monocyte infiltration in the vessel wall induced by resistin and could be proposed as therapeutic targets in reducing vessel wall inflammation. Stage 3 Project implementation during January to December was carried out by performing Stage 3: Investigation of the role of subendothelial resistin in monocyte transmigration; analysis of monocyte and smooth muscle cells SMC phenotype induced by resistin and fractalkine and analysis of molecular mechanisms involved in macrophage-SMC cross-talk.

In the period mentioned above the first objective of the project was finalized with the execution of Task 1. Moreover, in the same period, were accomplished tasks 2. Validation of the functional role of resistin-induced chemokines Fk and MCP-1 in monocyte transmigration The results obtained in task 1. Int J Biochem Cell Biol. Epub Feb 6.

Recently, high local resistin in the arterial vessel wall was shown to contribute to an enhanced accumulation of macrophages by mechanisms that need to be clarified.

Since in the vessel wall both endothelial genetic cancer drug targets EC and SMC respond to cytokines and promote atherosclerosis, we questioned whether subendothelial resistin sR has a role in vascular cells cross-talk leading to enhanced monocyte transmigration and we investigated the mechanisms involved. To this purpose we used an in vitro system of co-cultured SMC and EC activated by sR and we analyzed monocyte transmigration.

Our study indicates new possible targets for therapy to reduce resistin-dependent enhanced macrophage infiltration in the genetic cancer drug targets arterial wall. During January to December the Objective 2 of the project was implemented with the execution of Task 2. SMC were co-cultured with macrophages in presence or absence of resistin R or fractalkine FKN in a double chamber culture system for days.

The control cells are macrophages or SMCs grown separately no co-culture. In this co-culture system, the macrophages obtained genetic cancer drug targets differentiation of THP-1 with PMA nM for 3 days are cultured on the bottom of culture plate and the SMCs on the insert filter pore diameter 0.

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Co-culture is achieved genetic cancer drug targets placing the insert into the culture plate. Gene expression was quantified by the ΔΔCt algorithm. Cell culture lysates are diluted and mixed with a cocktail of biotinylated detection antibodies. Following a wash to remove unbound material, Streptavidin-HRP and chemiluminescent detection reagents are added sequentially. The activities are described in the scientific report of stage 4. Task 2.

Background and scientific results Resistin is a cytokine that in humans is secreted by peripheral blood mononuclear cells and macrophages. Serum resistin levels are elevated in patients with obesity-associated diabetes or cardiovascular disease.

Resistin was found in human atherosclerotic lesions and was suggested to be an inflammatory marker of atherosclerosis and to promote atherogenesis. Fractalkine FKN has dual function acting as a cell adhesion molecule and chemokine mediating direct capture, firm adhesion and transmigration of leukocytes and its expression is enhanced in human atherosclerotic plaques.

The objective of this study was to explore the role of resistin and FKN in macrophage-SMC cross-talk and to uncover the molecular mechanisms involved. To this purpose, THP-1 cells a monocytic cell line were differentiated to macrophages with phorbol myristate acetate PMA and then interacted with SMC cultured on membrane inserts in the presence or absence of resistin or FKN.

Macrophages alone or macrophages activated with resistin or FKN were used as controls. Our preliminary data indicate that FKN also modulate macrophage-SMC interaction by increasing the expression of mediators involved in inflammation and fibrosis.

In conclusion, the results of Task 2. Along atheroma development, the phenotype of macrophages and SMCs changes and may influence the disease progression.


The genetic cancer drug targets data on the phenotypes exhibited by these cells within atherosclerotic lesions raise many questions, regarding the mechanisms and factors that might control the transition of cell phenotype. SMCs often reside in vascular lesions in close proximity to macrophage clusters and are genetic cancer drug targets likely influenced by factors released from these pro-inflammatory phagocytes.

Moreover, macrophages may be influenced by direct contact with smooth muscle cells or soluble factors released by these cells.

Particularly, macrophages may promote activation and induce pro-atherogenic functions of SMCs and smooth muscle cells may modulate macrophage phenotype. Addressing the mechanisms involved in SMC-macrophages cross-talk that lead to phenotypic modulation of both cell types may provide new insight into atherogenesis and new targets for therapies of various vascular diseases.

The results of Task 2. Some of the results of Task 2. This activity is described in the scientific report of stage 4. Materials and methods Preparation of lipid nanoemulsions LN Lipid nanoemulsions LN were prepared using the ultrasonication method.

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Briefly, the organic and the aqueous phase were prepared separately. The obtained nanoemulsion was further vacuum evaporated, in order to eliminate the organic solvent traces. The formulation of nanoemulsions has been optimized by genetic cancer drug targets the concentration of surfactants. Briefly, the Psel peptide was activated by adding a reducing agent to break the disulfide bonds TCEP Buffer and mixed for 2 hours at room temperature.

At the end, to saturate the uncoupled maleimide groups, L-cysteine 1mM was added for 30 min. As a genetic cancer drug targets step, we performed centrifugation using Amicon ultracentrifugal filter units of kDa Millipore, Billerica, Massachusetts, USA in order to separate the  uncoupled Psel peptide and L-cysteine. By this step, the excess of Tween and glycerine are either filtrated or retained by the ultra-filtration membrane.

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P-selectin is a cell adhesion molecule highly expressed by endothelium in inflammation, and therefore a potential target for nanotherapy.

We hypothesize that functionalization of nanoparticles with P-selectin high affinity peptide will increase their binding to activated endothelium in inflamed tissues. Thus, the aim of this study was to develop nanoparticles loaded with curcumin Cm, a hydrophobic anti-inflammatory polyphenol that are able to target the inflammatory process in both, acute and chronic inflammation.