Publications by authors named "Laurent Martiny"

59 Publications

Adverse Effects of Oseltamivir Phosphate Therapy on the Liver of LDLR-/- Mice Without Any Benefit on Atherosclerosis and Thrombosis.

J Cardiovasc Pharmacol 2021 May;77(5):660-672

UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Reims, France.

Abstract: Desialylation, governed by sialidases or neuraminidases, is strongly implicated in a wide range of human disorders, and accumulative data show that inhibition of neuraminidases, such as neuraminidases 1 sialidase, may be useful for managing atherosclerosis. Several studies have reported promising effects of oseltamivir phosphate, a widely used anti-influenza sialidase inhibitor, on human cancer cells, inflammation, and insulin resistance. In this study, we evaluated the effects of oseltamivir phosphate on atherosclerosis and thrombosis and potential liver toxicity in LDLR-/- mice fed with high-fat diet. Our results showed that oseltamivir phosphate significantly decreased plasma levels of LDL cholesterol and elastin fragmentation in aorta. However, no effect was observed on both atherosclerotic plaque size in aortic roots and chemically induced thrombosis in carotid arteries. Importantly, oseltamivir phosphate administration had adverse effects on the liver of mice and significantly increased messenger RNA expression levels of F4/80, interleukin-1β, transforming growth factor-β1, matrix metalloproteinase-12, and collagen. Taken together, our findings suggest that oseltamivir phosphate has limited benefits on atherosclerosis and carotid thrombosis and may lead to adverse side effects on the liver with increased inflammation and fibrosis.
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http://dx.doi.org/10.1097/FJC.0000000000001002DOI Listing
May 2021

Anti-Tumoral and Anti-Angiogenic Effects of Low-Diluted on Melanoma.

Front Oncol 2021 3;11:597503. Epub 2021 Mar 3.

Université de Reims-Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France.

Melanoma is the most aggressive form of skin cancer and the most rapidly expanding cancer in terms of worldwide incidence. If primary cutaneous melanoma is mostly treated with a curative wide local excision, malignant melanoma has a poor prognosis and needs other therapeutic approaches. Angiogenesis is a normal physiological process essential in growth and development, but it also plays a crucial role in crossing from benign to advanced state in cancer. In melanoma progression, angiogenesis is widely involved during the vertical growth phase. Currently, no anti-angiogenic agents are efficient on their own, and combination of treatments will probably be the key to success. In the past, phenacetin was used as an analgesic to relieve pain, causing side effects at large dose and tumor-inducing in humans and animals. By contrast, low-dilution is often used in skin febrile exanthema, patches profusely scattered on limbs, headache, or flushed face without side effects. Herein are described the , , and anti-angiogenic and anti-tumoral potentials of low-dilution in a B16F1 tumor model and endothelial cells. We demonstrate that low-diluted inhibits tumor growth and tumor vascularization and thus increases the survival time of B16F1 melanoma induced-C57BL/6 mice. Moreover, modulates the lung metastasis in a B16F10 induced model. and , we evidence that low-diluted inhibits the migration and the recruitment of endothelial cells and leads to an imbalance in the pro-tumoral macrophages and to a structural malformation of the vascular network. All together these results demonstrate highly hopeful anti-tumoral, anti-metastatic, and anti-angiogenic effects of low-dilution on melanoma. Continued studies are needed to preclinically validate low-dilution as a complementary or therapeutic strategy for melanoma treatment.
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http://dx.doi.org/10.3389/fonc.2021.597503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966719PMC
March 2021

Revealing the elasticity of an individual aortic fiber during ageing at nanoscale by in situ atomic force microscopy.

Nanoscale 2021 Jan 5;13(2):1124-1133. Epub 2021 Jan 5.

Laboratoire de Recherche en Nanosciences, LRN EA4682, University of Reims Champagne-Ardenne, 51685 Reims, France.

Arterial stiffness is a complex process affecting the aortic tree that significantly contributes to cardiovascular diseases (systolic hypertension, coronary artery disease, heart failure or stroke). This process involves a large extracellular matrix remodeling mainly associated with elastin content decrease and collagen content increase. Additionally, various chemical modifications that accumulate with ageing have been shown to affect long-lived assemblies, such as elastic fibers, that could affect their elasticity. To precisely characterize the fiber changes and the evolution of its elasticity with ageing, high resolution and multimodal techniques are needed for precise insight into the behavior of a single fiber and its surrounding medium. In this study, the latest developments in atomic force microscopy and the related nanomechanical modes are used to investigate the evolution and in a near-physiological environment, the morphology and elasticity of aorta cross sections obtained from mice of different ages with an unprecedented resolution. In correlation with more classical approaches such as pulse wave velocity and fluorescence imaging, we demonstrate that the relative Young's moduli of elastic fibers, as well as those of the surrounding areas, significantly increase with ageing. This nanoscale characterization presents a new view on the stiffness process, showing that, besides the elastin and collagen content changes, elasticity is impaired at the molecular level, allowing a deeper understanding of the ageing process. Such nanomechanical AFM measurements of mouse tissue could easily be applied to studies of diseases in which elastic fibers suffer pathologies such as atherosclerosis and diabetes, where the precise quantification of fiber elasticity could better follow the fiber remodeling and predict plaque rupture.
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http://dx.doi.org/10.1039/d0nr06753aDOI Listing
January 2021

Thrombospondin-1 Receptor CD47 Overexpression Contributes to P-Glycoprotein-Mediated Multidrug Resistance Against Doxorubicin in Thyroid Carcinoma FTC-133 Cells.

Front Oncol 2020 7;10:551228. Epub 2020 Dec 7.

UMR-CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne Ardenne, Moulin de la Housse, Reims, France.

It is now admitted that in addition to acquired resistance, the tumor microenvironment contributes to the development of chemo-resistance and malignant progression. In a previous study, we showed that Dox induced apoptosis in FTC-133 cells by trigging JNK pathway. This process was accompanied by a decrease of thrombospondin-1 (TSP-1) expression. Moreover, exogenous TSP-1 or its C-terminal-derived peptide interact with receptor CD47 and are able to protect FTC-133 cells against Dox-induced apoptosis. Here, we investigated the involvement of TSP-1/CD47 interaction in a context of acquired multidrug resistance in FTC-133 cells. To that end, we established a Dox-resistant cell line (FTC-133R cells) which developed a resistance against Dox-induced apoptosis. Cell viability was evaluated by Uptiblue assay, nuclear Dox was measured by microspectrofluorimetry, caspase activity was measured by fluorescence of cleaved caspase-3 substrate, gene expression was evaluated by RT-PCR and protein expression was examined by western-blot. Our results showed that FTC-133R overexpressed the P-gp and were 15-fold resistant to Dox. JNK phosphorylation and Dox-induced apoptosis were reduced in FTC-133R cells. Expression of CD47 was increased in FTC-133R cells but TSP-1 expression presented similar levels in two cell lines. VPL restored Dox nuclear uptake and FTC-133R cell sensitivity to apoptosis and induced a decrease in CD47 mRNA expression. Moreover, knockdown of CD47 in FTC-133R cells induced an increase in JNK activation and sensitized FTC-133R cells to Dox. Our data suggest that CD47 is able to contribute to the protection of FTC-133R cells against Dox-induced apoptosis and/or to potentiate the acquired Dox resistance.
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http://dx.doi.org/10.3389/fonc.2020.551228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750475PMC
December 2020

Towards the Therapeutic Use of Thrombospondin 1/CD47 Targeting TAX2 Peptide as an Antithrombotic Agent.

Arterioscler Thromb Vasc Biol 2021 01 24;41(1):e1-e17. Epub 2020 Nov 24.

UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Reims, France (A.J., T.S., M.C., C.K., L.M., P.M., S.D.).

Objective: TSP-1 (thrombospondin 1) is one of the most expressed proteins in platelet α-granules and plays an important role in the regulation of hemostasis and thrombosis. Interaction of released TSP-1 with CD47 membrane receptor has been shown to regulate major events leading to thrombus formation, such as, platelet adhesion to vascular endothelium, nitric oxide/cGMP (cyclic guanosine monophosphate) signaling, platelet activation as well as aggregation. Therefore, targeting TSP-1:CD47 axis may represent a promising antithrombotic strategy. Approach and Results: A CD47-derived cyclic peptide was engineered, namely TAX2, that targets TSP-1 and selectively prevents TSP-1:CD47 interaction. Here, we demonstrate for the first time that TAX2 peptide strongly decreases platelet aggregation and interaction with collagen under arterial shear conditions. TAX2 also delays time for complete thrombotic occlusion in 2 mouse models of arterial thrombosis following chemical injury, while mice recapitulate TAX2 effects. Importantly, TAX2 administration is not associated with increased bleeding risk or modification of hematologic parameters.

Conclusions: Overall, this study sheds light on the major contribution of TSP-1:CD47 interaction in platelet activation and thrombus formation while putting forward TAX2 as an innovative antithrombotic agent with high added-value.
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http://dx.doi.org/10.1161/ATVBAHA.120.314571DOI Listing
January 2021

Lactosylceramide induced by elastin-derived peptides decreases adipocyte differentiation.

J Physiol Biochem 2020 Aug 26;76(3):457-467. Epub 2020 Jun 26.

UMR CNRS 7369 MEDyC, SFR CAP-Sante, Université de Reims Champagne-Ardenne, Reims, France.

Elastin, the major protein of the extracellular matrix, is specially found in cardiovascular tissues and contributing to 30-50% of the dry weight of blood vessels. Elastin regulates cell signalling pathways involved in morphogenesis, injury response and inflammation. The function of elastin is frequently compromised in damaged or aged elastic tissues. Indeed, elastin degradation, observed during ageing, and the resulting production of elastin-derived peptides (EDPs), have crucial impacts on cardiovascular disease (atherosclerosis, thrombosis) or on metabolism disease progressions (type 2 diabetes or non-alcoholic steatohepatitis). In the present study, we analysed the EDP effects on 3T3 preadipocyte cell differentiation. In a first part, we treated 3T3-L1 cells with EDP and visualized the lipid droplet accumulation by the oil red O staining and measured the expression of various transcription factors and adipocyte-specific mRNAs by real-time RT-PCR. We demonstrated that the elastin receptor complex, ERC, is activated by EDPs and decreased adipocyte differentiation by a modulation of crucial adipogenesis transcriptional factor particularly PPARγ. In a second part, we identified the signalling pathway implicated in EDP-reduced cell differentiation. The flow cytometry and immunocytochemistry approaches showed that ERC activated by EDP produced a second messenger, lactosylceramide (Lac-Cer). Moreover, this Lac-Cer production favoured the phosphorylation of ERK1-2 (p-ERK1-2), to decrease adipocyte differentiation by a modulation of adipogenesis transcriptional factor PPARγ. To conclude, the EDP/Lac-Cer/p-ERK1-2 signalling pathway may be studied further as a critical target for treating complications associated with adipocyte dedifferentiation such as obesity and diabetes insulin resistance.
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http://dx.doi.org/10.1007/s13105-020-00755-zDOI Listing
August 2020

Low-diluted Phenacetinum disrupted the melanoma cancer cell migration.

Sci Rep 2019 06 24;9(1):9109. Epub 2019 Jun 24.

CNRS UMR7369 MEDyC, University of Reims Champagne-Ardenne, Reims, France.

Dynamic and reciprocal interactions generated by the communication between tumor cells and their matrix microenvironment, play a major role in the progression of a tumor. Indeed, the adhesion of specific sites to matrix components, associated with the repeated and coordinated formation of membrane protrusions, allow tumor cells to move along a determined pathway. Our study analyzed the mechanism of action of low-diluted Phenacetinum on murine cutaneous melanoma process in a fibronectin matrix environment. We demonstrated a reduction of dispersed cell migration, early and for as long as 24 h, by altering the formation of cell protrusions. Moreover, low-diluted Phenacetinum decreased cell stiffness highly on peripheral areas, due to a disruption of actin filaments located just under the plasma membrane. Finally, it modified the structure of the plasma membrane by accumulating large ordered lipid domains and disrupted B16 cell migration by a likely shift in the balance between ordered and disordered lipid phases. Whereas the correlation between the excess of lipid raft and cytoskeleton disrupting is not as yet established, it is clear that low-diluted Phenacetinum acts on the actin cytoskeleton organization, as confirmed by a decrease of cell stiffness affecting ultimately the establishment of an effective migration process.
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http://dx.doi.org/10.1038/s41598-019-45578-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591484PMC
June 2019

Elastic fibers and elastin receptor complex: Neuraminidase-1 takes the center stage.

Matrix Biol 2019 11 18;84:57-67. Epub 2019 Jun 18.

UMR CNRS 7369 MEDyC, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Reims, France. Electronic address:

Extracellular matrix (ECM) has for a long time being considered as a simple architectural support for cells. It is now clear that ECM presents a fundamental influence on cells driving their phenotype and fate. This complex network is highly specialized and the different classes of macromolecules that comprise the ECM determine its biological functions. For instance, collagens are responsible for the tensile strength of tissues, proteoglycans and glycosaminoglycans are essential for hydration and resistance to compression, and glycoproteins such as laminins facilitate cell attachment. The largest structures of the ECM are the elastic fibers found in abundance in tissues suffering high mechanical constraints such as skin, lungs or arteries. These structures present a very complex composition whose core is composed of elastin surrounded by a microfibrils mantle. Elastogenesis is a tightly regulated process involving the sialidase activity of the Neuraminidase-1 (Neu-1) sub-unit of the Elastin Receptor Complex. Interestingly, Neu-1 subunit also serves as a sensor of elastin degradation via its ability to transmit elastin-derived peptides signaling. Finally, reports showing that neuraminidase activity is able to regulate TGF-β activation raises questions about a possible role for Neu-1 in elastic fibers remodeling. In this mini review, we develop the concept of the regulation of the whole life of elastic fibers through an original scope, the key role of Neu-1 sialidase enzymatic activity.
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http://dx.doi.org/10.1016/j.matbio.2019.06.007DOI Listing
November 2019

Role of elastin peptides and elastin receptor complex in metabolic and cardiovascular diseases.

FEBS J 2019 08 11;286(15):2980-2993. Epub 2019 Apr 11.

UMR CNRS 7369 MEDyC, SFR CAP-Santé, Université de Reims Champagne-Ardenne, France.

The Cardiovascular Continuum describes a sequence of events from cardiovascular risk factors to end-stage heart disease. It includes conventional pathologies affecting cardiovascular functions such as hypertension, atherosclerosis or thrombosis and was traditionally considered from the metabolic point of view. This Cardiovascular Continuum, originally described by Dzau and Braunwald, was extended by O'Rourke to consider also the crucial role played by degradation of elastic fibers, occurring during aging, in the appearance of vascular stiffness, another deleterious risk factor of the continuum. However, the involvement of the elastin degradation products, named elastin-derived peptides, to the Cardiovascular Continuum progression has not been considered before. Data from our laboratory and others clearly showed that these bioactive peptides are central regulators of this continuum, thereby amplifying appearance and evolution of cardiovascular risk factors such as diabetes or hypertension, of vascular alterations such as atherothrombosis and calcification, but also nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. The Elastin Receptor Complex has been shown to be a crucial actor in these processes. We propose here the participation of these elastin-derived peptides and of the Elastin Receptor Complex in these events, and introduce a revisited Cardiovascular Continuum based on their involvement, for which elastin-based pharmacological strategies could have a strong impact in the future.
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http://dx.doi.org/10.1111/febs.14836DOI Listing
August 2019

Correction: Thrombospondin-targeting TAX2 peptide impairs tumor growth in preclinical mouse models of childhood neuroblastoma.

Pediatr Res 2019 Apr;85(5):734

Universite de Reims Champagne-Ardenne, UFR Sciences Exactes et Naturelles, Reims, France.

The authors "Revital Rattenbach", "ltschak Lamensdorf", and "Celine Martin" were not included in the author list of this published article however should be considered to be authors since they contributed substantially to the work. The updated author list of this article can be found in the associated correction.
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http://dx.doi.org/10.1038/s41390-019-0329-4DOI Listing
April 2019

Identification of CD36 as a new interaction partner of membrane NEU1: potential implication in the pro-atherogenic effects of the elastin receptor complex.

Cell Mol Life Sci 2019 Feb 29;76(4):791-807. Epub 2018 Nov 29.

UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 "Matrix Aging and Vascular Remodelling", Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Moulin de la Housse, BP1039, 51687, Reims Cedex 2, France.

In addition to its critical role in lysosomes for catabolism of sialoglycoconjugates, NEU1 is expressed at the plasma membrane and regulates a myriad of receptors by desialylation, playing a key role in many pathophysiological processes. Here, we developed a proteomic approach dedicated to the purification and identification by LC-MS/MS of plasma membrane NEU1 interaction partners in human macrophages. Already known interaction partners were identified as well as several new candidates such as the class B scavenger receptor CD36. Interaction between NEU1 and CD36 was confirmed by complementary approaches. We showed that elastin-derived peptides (EDP) desialylate CD36 and that this effect was blocked by the V14 peptide, which blocks the interaction between bioactive EDP and the elastin receptor complex (ERC). Importantly, EDP also increased the uptake of oxidized LDL by macrophages that is blocked by both the V14 peptide and the sialidase inhibitor 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA). These results demonstrate, for the first time, that binding of EDP to the ERC indirectly modulates CD36 sialylation level and regulates oxidized LDL uptake through this sialidase. These effects could contribute to the previously reported proatherogenic role of EDP and add a new dimension in the regulation of biological processes through NEU1.
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http://dx.doi.org/10.1007/s00018-018-2978-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514072PMC
February 2019

Elastin molecular aging promotes MDA-MB-231 breast cancer cell invasiveness.

FEBS Open Bio 2018 Sep 2;8(9):1395-1404. Epub 2018 Aug 2.

UMR CNRS/URCA 7369 SFR CAP Santé Faculty of Sciences University of Reims Champagne-Ardenne France.

Elastin is a long-lived extracellular matrix protein responsible for the structural integrity and function of tissues. Breast cancer elastosis is a complex phenomenon resulting in both the deposition of elastotic masses and the local production of elastin fragments. In invasive human breast cancers, an increase in elastosis is correlated with severity of the disease and age of the patient. Elastin-derived peptides (EDPs) are a hallmark of aging and are matrikines - matrix fragments having the ability to regulate cell physiology. They are known to promote processes linked to tumor progression, but their effects on breast cancer cells remain unexplored. Our data show that EDPs enhance the invasiveness of MDA-MB-231 breast cancer cells through the engagement of matrix metalloproteases 14 and 2. We therefore suggest that elastosis and/or an aged stroma could promote breast cancer cell invasiveness.
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http://dx.doi.org/10.1002/2211-5463.12455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120250PMC
September 2018

Production of Elastin-Derived Peptides Contributes to the Development of Nonalcoholic Steatohepatitis.

Diabetes 2018 08 25;67(8):1604-1615. Epub 2018 May 25.

UMR CNRS 7369 MEDyC, University of Reims Champagne-Ardenne, Reims, France

Affecting more than 30% of the Western population, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic steatohepatitis (NASH), cancer, hypertension, and atherosclerosis. Insulin resistance and obesity are described as potential causes of NAFLD. However, we surmised that factors such as extracellular matrix remodeling of large blood vessels, skin, or lungs may also participate in the progression of liver diseases. We studied the effects of elastin-derived peptides (EDPs), biomarkers of aging, on NAFLD progression. We evaluated the consequences of EDP accumulation in mice and of elastin receptor complex (ERC) activation on lipid storage in hepatocytes, inflammation, and fibrosis development. The accumulation of EDPs induces hepatic lipogenesis (i.e., SREBP1c and ACC), inflammation (i.e., Kupffer cells, IL-1β, and TGF-β), and fibrosis (collagen and elastin expression). These effects are induced by inhibition of the LKB1-AMPK pathway by ERC activation. In addition, pharmacological inhibitors of EDPs demonstrate that this EDP-driven lipogenesis and fibrosis relies on engagement of the ERC. Our data reveal a major role of EDPs in the development of NASH, and they provide new clues for understanding the relationship between NAFLD and vascular aging.
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http://dx.doi.org/10.2337/db17-0490DOI Listing
August 2018

Molecular analysis of differential antiproliferative activity of resveratrol, epsilon viniferin and labruscol on melanoma cells and normal dermal cells.

Food Chem Toxicol 2018 Jun 22;116(Pt B):323-334. Epub 2018 Apr 22.

Université de Bourgogne, Dijon F-21000, France; Inserm Research Center U1231, "Cancer and Adaptative Immune Response", Bioactive Molecules and Health Research Group, Dijon F-21000, France. Electronic address:

Very recently, we have produced new resveratrol derived compounds, especially labruscol by culture of elicited grapevine cell suspensions (Vitis labrusca L.). This new polyphenolic oligomer could function as cancer chemopreventive agent in similar manner of resveratrol. In this study, we have determined the efficiency of resveratrol, ε-viniferin and the labruscol on human melanoma cell with or without metastatic phenotype. Our results show a differential activity of the three compounds where the resveratrol remains the polyphenolic compound with the most effective action compared to other oligomers. These three compounds block cell cycle of melanoma cells in S phase by modulating key regulators of cell cycle i.e. cyclins A, E, D1 and their cyclin-dependent kinases 1 and 2. These effects are associated with an increase of cell death while these compounds have no cytotoxic action on normal human dermal fibroblasts.
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http://dx.doi.org/10.1016/j.fct.2018.04.043DOI Listing
June 2018

Cytotoxicity of Labruscol, a New Resveratrol Dimer Produced by Grapevine Cell Suspensions, on Human Skin Melanoma Cancer Cell Line HT-144.

Molecules 2017 Nov 9;22(11). Epub 2017 Nov 9.

Unité Matrice Extracellulaire et Dynamique Cellulaire, UMR CNRS 7369, SFR Cap-Santé FED 4231, UFR des Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, BP 1039, 51687 Reims CEDEX 2, France.

A new resveratrol dimer () called labruscol, has been purified by centrifugal partition chromatography of a crude ethyl acetate stilbene extract obtained from elicited grapevine cell suspensions of L. cultured in a 14-liter stirred bioreactor. One dimensional (1D) and two dimensional (2D) nuclear magnetic resonance (NMR) analyses including ¹H, C, heteronuclear single-quantum correlation HSQC), heteronuclear multiple bond correlation (HMBC), and correlation spectroscopy (COSY) as well as high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS) were used to characterize this compound and to unambiguously identify it as a new stilbene dimer, though its relative stereochemistry remained unsolved. Labruscol was recovered as a pure compound (>93%) in sufficient amounts (41 mg) to allow assessment of its biological activity (cell viability, cell invasion and apoptotic activity) on two different cell lines, including one human skin melanoma cancer cell line HT-144 and a healthy human dermal fibroblast (HDF) line. This compound induced almost 100% of cell viability inhibition in the cancer line at a dose of 100 μM within 72 h of treatment. However, at all tested concentrations and treatment times, resveratrol displayed an inhibition of the cancer line viability higher than that of labruscol in the presence of fetal bovine serum. Both compounds also showed differential activities on healthy and cancer cell lines. Finally, labruscol at a concentration of 1.2 μM was shown to reduce cell invasion by 40%, although no similar activity was observed with resveratrol. The cytotoxic activity of this newly-identified dimer is discussed.
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http://dx.doi.org/10.3390/molecules22111940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150286PMC
November 2017

Lumican delays melanoma growth in mice and drives tumor molecular assembly as well as response to matrix-targeted TAX2 therapeutic peptide.

Sci Rep 2017 08 9;7(1):7700. Epub 2017 Aug 9.

Université de Reims Champagne-Ardenne, UFR Sciences Exactes et Naturelles, Campus Moulin de la Housse, 51100, Reims, France.

Lumican is a small leucine-rich proteoglycan (SLRP) being known as a key regulator of collagen fibrillogenesis. However, little attention has been given so far in studying its influence on tumor-associated matrix architecture. Here, we investigate the role of host lumican on tumor matrix organization as well as on disease progression considering an immunocompetent model of melanoma implanted in Lum vs. wild type syngeneic mice. Conjointly, lumican impact on tumor response to matrix-targeted therapy was evaluated considering a previously validated peptide, namely TAX2, that targets matricellular thrombospondin-1. Analysis of available genomics and proteomics databases for melanoma first established a correlation between lumican expression and patient outcome. In the B16 melanoma allograft model, endogenous lumican inhibits tumor growth and modulates response to TAX2 peptide. Indeed, IHC analyses revealed that lumican deficiency impacts intratumoral distribution of matricellular proteins, growth factor and stromal cells. Besides, innovative imaging approaches helped demonstrating that lumican host expression drives biochemical heterogeneity of s.c. tumors, while modulating intratumoral collagen deposition as well as organization. Altogether, the results obtained present lumican as a strong endogenous inhibitor of tumor growth, while identifying for the first time this proteoglycan as a major driver of tumor matrix coherent assembly.
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http://dx.doi.org/10.1038/s41598-017-07043-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550434PMC
August 2017

Intrinsic dynamics study identifies two amino acids of TIMP-1 critical for its LRP-1-mediated endocytosis in neurons.

Sci Rep 2017 07 14;7(1):5375. Epub 2017 Jul 14.

CNRS UMR 7369: Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne (URCA), Laboratoire SiRMa - Campus Moulin de la Housse, BP 1039, 51687, Reims cedex, France.

The tissue inhibitor of metalloproteinases-1 (TIMP-1) exerts inhibitory activity against matrix metalloproteinases and cytokine-like effects. We previously showed that TIMP-1 reduces neurite outgrowth in mouse cortical neurons and that this cytokine-like effect depends on TIMP-1 endocytosis mediated by the low-density lipoprotein receptor-related protein-1 (LRP-1). To gain insight into the interaction between TIMP-1 and LRP-1, we considered conformational changes that occur when a ligand binds to its receptor. TIMP-1 conformational changes have been studied using biomolecular simulations, and our results provide evidence for a hinge region that is critical for the protein movement between the N- and C-terminal TIMP-1 domains. In silico mutants have been proposed on residues F12 and K47, which are located in the hinge region. Biological analyses of these mutants show that F12A or K47A mutation does not alter MMP inhibitory activity but impairs the effect of TIMP-1 on neurite outgrowth. Interestingly, these mutants bind to LRP-1 but are not endocytosed. We conclude that the intrinsic dynamics of TIMP-1 are not involved in its binding to LRP-1 but rather in the initiation of endocytosis and associated biological effects.
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http://dx.doi.org/10.1038/s41598-017-05039-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511134PMC
July 2017

Anti-Cancer Activity of Resveratrol and Derivatives Produced by Grapevine Cell Suspensions in a 14 L Stirred Bioreactor.

Molecules 2017 Mar 16;22(3). Epub 2017 Mar 16.

Unité Matrice Extracellulaire et Dynamique Cellulaire, UMR CNRS 7369, SFR Cap-Santé FED 4231, UFR des Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne, BP 1039, 51687 Reims CEDEX 2, France.

In the present study, resveratrol and various oligomeric derivatives were obtained from a 14 L bioreactor culture of elicited grapevine cell suspensions (Vitis labrusca L.). The crude ethyl acetate stilbene extract obtained from the culture medium was fractionated by centrifugal partition chromatography (CPC) using a gradient elution method and the major stilbenes contained in the fractions were subsequently identified by using a C-NMR-based dereplication procedure and further 2D NMR analyses including HSQC, HMBC, and COSY. Beside δ-viniferin (2), leachianol F (4) and G (4'), four stilbenes (resveratrol (1), ε-viniferin (5), pallidol (3) and a newly characterized dimer (6)) were recovered as pure compounds in sufficient amounts to allow assessment of their biological activity on the cell growth of three different cell lines, including two human skin malignant melanoma cancer cell lines (HT-144 and SKMEL-28) and a healthy human dermal fibroblast HDF line. Among the dimers obtained in this study, the newly characterized resveratrol dimer (6) has never been described in nature and its biological potential was evaluated here for the first time. ε-viniferin as well as dimer (6) showed IC values on the three tested cell lines lower than the ones exerted by resveratrol and pallidol. However, activities of the first two compounds were significantly decreased in the presence of fetal bovine serum although that of resveratrol and pallidol was not. The differential tumor activity exerted by resveratrol on healthy and cancer lines was also discussed.
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http://dx.doi.org/10.3390/molecules22030474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155302PMC
March 2017

New Insights into Molecular Organization of Human Neuraminidase-1: Transmembrane Topology and Dimerization Ability.

Sci Rep 2016 12 5;6:38363. Epub 2016 Dec 5.

Laboratoire Signalisation et Récepteurs Matriciels (SiRMa), UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Reims, France.

Neuraminidase 1 (NEU1) is a lysosomal sialidase catalyzing the removal of terminal sialic acids from sialyloconjugates. A plasma membrane-bound NEU1 modulating a plethora of receptors by desialylation, has been consistently documented from the last ten years. Despite a growing interest of the scientific community to NEU1, its membrane organization is not understood and current structural and biochemical data cannot account for such membrane localization. By combining molecular biology and biochemical analyses with structural biophysics and computational approaches, we identified here two regions in human NEU1 - segments 139-159 (TM1) and 316-333 (TM2) - as potential transmembrane (TM) domains. In membrane mimicking environments, the corresponding peptides form stable α-helices and TM2 is suited for self-association. This was confirmed with full-size NEU1 by co-immunoprecipitations from membrane preparations and split-ubiquitin yeast two hybrids. The TM2 region was shown to be critical for dimerization since introduction of point mutations within TM2 leads to disruption of NEU1 dimerization and decrease of sialidase activity in membrane. In conclusion, these results bring new insights in the molecular organization of membrane-bound NEU1 and demonstrate, for the first time, the presence of two potential TM domains that may anchor NEU1 in the membrane, control its dimerization and sialidase activity.
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http://dx.doi.org/10.1038/srep38363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137157PMC
December 2016

Thrombospondin-targeting TAX2 peptide impairs tumor growth in preclinical mouse models of childhood neuroblastoma.

Pediatr Res 2017 03 14;81(3):480-488. Epub 2016 Nov 14.

Université de Reims Champagne-Ardenne, UFR Sciences Exactes et Naturelles, Reims, France.

Background: We have previously identified TAX2 peptide as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with the cell-surface receptor CD47. TAX2 displays exciting antiangiogenic, antitumor, and antimetastatic properties in both allograft and xenograft models of melanoma as well as pancreatic carcinoma. Here, TAX2 therapeutic potential was investigated in two distinct preclinical mouse models of neuroblastoma.

Methods: SK-N-BE(2) (MYCN-amplified) and SK-N-SH (MYCN-negative) human neuroblastoma cells have been implanted in outbred NMRI nude mice prior to systemic administrations of TAX2, and then tumor growth as well as intratumoral blood flow were longitudinally monitored. At study termination, subcutaneous xenografts were macroscopically and histopathologically examined.

Results: In both models, TAX2 induced a significant inhibition of tumor burden in mice engrafted with large pre-established neuroblastoma tumors. Indeed, TAX2 administered at biologically relevant doses sharply alters xenograft vascularization as well as multiple features of tumor progression.

Conclusion: Altogether, our results present TAX2 peptide specifically targeting TSP-1:CD47 interaction as a new putative therapeutic approach for treating neuroblastoma, whether utilized alone or in combination with existing chemotherapy drugs.
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http://dx.doi.org/10.1038/pr.2016.242DOI Listing
March 2017

Impact of sialic acids on the molecular dynamic of bi-antennary and tri-antennary glycans.

Sci Rep 2016 10 19;6:35666. Epub 2016 Oct 19.

Université de Reims Champagne-Ardenne, UMR CNRS 7369, "Matrice Extracellulaire et Dynamique Cellulaire", UFR Sciences Exactes et Naturelles, Chemin des Rouliers, 51100 Reims, France.

Sialic acids (SA) are monosaccharides that can be located at the terminal position of glycan chains on a wide range of proteins. The post-translational modifications, such as N-glycan chains, are fundamental to protein functions. Indeed, the hydrolysis of SA by specific enzymes such as neuraminidases can lead to drastic modifications of protein behavior. However, the relationship between desialylation of N-glycan chains and possible alterations of receptor function remains unexplored. Thus, the aim of the present study is to establish the impact of SA removal from N-glycan chains on their conformational behavior. We therefore undertook an in silico investigation using molecular dynamics to predict the structure of an isolated glycan chain. We performed, for the first time, 3 independent 500 ns simulations on bi-antennary and tri-antennary glycan chains displaying or lacking SA. We show that desialylation alters both the preferential conformation and the flexibility of the glycan chain. This study suggests that the behavior of glycan chains induced by presence or absence of SA may explain the changes in the protein function.
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http://dx.doi.org/10.1038/srep35666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069492PMC
October 2016

Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide.

Clin Exp Metastasis 2016 10 27;33(7):637-49. Epub 2016 Jun 27.

Laboratoire SiRMa, Campus Moulin de La Housse, Université de Reims Champagne-Ardenne (URCA), UFR Sciences Exactes Et Naturelles, BP 1039, 51687, Reims Cedex 2, France.

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.
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http://dx.doi.org/10.1007/s10585-016-9803-0DOI Listing
October 2016

Matrix ageing and vascular impacts: focus on elastin fragmentation.

Cardiovasc Res 2016 06 22;110(3):298-308. Epub 2016 Mar 22.

Team 2: Matrix aging and Vascular remodelling, UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), UFR Sciences Exactes et Naturelles, Reims, France

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and represent a major problem of public health. Over the years, life expectancy has considerably increased throughout the world, and the prevalence of CVD is inevitably rising with the growing ageing of the population. The normal process of ageing is associated with progressive deterioration in structure and function of the vasculature, commonly called vascular ageing. At the vascular level, extracellular matrix (ECM) ageing leads to molecular alterations in long half-life proteins, such as elastin and collagen, and have critical effects on vascular diseases. This review highlights ECM alterations occurring during vascular ageing with a specific focus on elastin fragmentation and also the contribution of elastin-derived peptides (EDP) in age-related vascular complications. Moreover, current and new pharmacological strategies aiming at minimizing elastin degradation, EDP generation, and associated biological effects are discussed. These strategies may be of major relevance for preventing and/or delaying vascular ageing and its complications.
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http://dx.doi.org/10.1093/cvr/cvw061DOI Listing
June 2016

The Elastin Receptor Complex: A Unique Matricellular Receptor with High Anti-tumoral Potential.

Front Pharmacol 2016 4;7:32. Epub 2016 Mar 4.

UMR CNRS/URCA 7369, SFR CAP Santé, Université de Reims Champagne Ardenne, Faculté des Sciences Reims, France.

Elastin, one of the longest-lived proteins, confers elasticity to tissues with high mechanical constraints. During aging or pathophysiological conditions such as cancer progression, this insoluble polymer of tropoelastin undergoes an important degradation leading to the release of bioactive elastin-derived peptides (EDPs), named elastokines. EDP exhibit several biological functions able to drive tumor development by regulating cell proliferation, invasion, survival, angiogenesis, and matrix metalloproteinase expression in various tumor and stromal cells. Although, several receptors have been suggested to bind elastokines (αvβ3 and αvβ5 integrins, galectin-3), their main receptor remains the elastin receptor complex (ERC). This heterotrimer comprises a peripheral subunit, named elastin binding protein (EBP), associated to the protective protein/cathepsin A (PPCA). The latter is bound to a membrane-associated protein called Neuraminidase-1 (Neu-1). The pro-tumoral effects of elastokines have been linked to their binding onto EBP. Additionally, Neu-1 sialidase activity is essential for their signal transduction. Consistently, EDP-EBP interaction and Neu-1 activity emerge as original anti-tumoral targets. Interestingly, besides its direct involvement in cancer progression, the ERC also regulates diabetes outcome and thrombosis, an important risk factor for cancer development and a vascular process highly increased in patients suffering from cancer. In this review, we will describe ERC and elastokines involvement in cancer development suggesting that this unique receptor would be a promising therapeutic target. We will also discuss the pharmacological concepts aiming at blocking its pro-tumoral activities. Finally, its emerging role in cancer-associated complications and pathologies such as diabetes and thrombotic events will be also considered.
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http://dx.doi.org/10.3389/fphar.2016.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777733PMC
March 2016

Original insights on thrombospondin-1-related antireceptor strategies in cancer.

Front Pharmacol 2015 29;6:252. Epub 2015 Oct 29.

Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Université de Reims Champagne-Ardenne Reims, France ; CNRS, Matrice Extracellulaire et Dynamique Cellulaire, UMR 7369 Reims, France.

Thrombospondin-1 (TSP-1) is a large matricellular glycoprotein known to be overexpressed within tumor stroma in several cancer types. While mainly considered as an endogenous angiogenesis inhibitor, TSP-1 exhibits multifaceted functionalities in a tumor context depending both on TSP-1 concentration as well as differential receptor expression by cancer cells and on tumor-associated stromal cells. Besides, the complex modular structure of TSP-1 along with the wide variety of its soluble ligands and membrane receptors considerably increases the complexity of therapeutically targeting interactions involving TSP-1 ligation of cell-surface receptors. Despite the pleiotropic nature of TSP-1, many different antireceptor strategies have been developed giving promising results in preclinical models. However, transition to clinical trials often led to nuanced outcomes mainly due to frequent severe adverse effects. In this review, we will first expose the intricate and even sometimes opposite effects of TSP-1-related signaling on tumor progression by paying particular attention to modulation of angiogenesis and tumor immunity. Then, we will provide an overview of current developments and prospects by focusing particularly on the cell-surface molecules CD47 and CD36 that function as TSP-1 receptors; including antibody-based approaches, therapeutic gene modulation and the use of peptidomimetics. Finally, we will discuss original approaches specifically targeting TSP-1 domains, as well as innovative combination strategies with a view to producing an overall anticancer response.
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http://dx.doi.org/10.3389/fphar.2015.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625054PMC
November 2015

Uncoupling of Elastin Complex Receptor during In Vitro Aging Is Related to Modifications in Its Intrinsic Sialidase Activity and the Subsequent Lactosylceramide Production.

PLoS One 2015 18;10(6):e0129994. Epub 2015 Jun 18.

Laboratoire Signalisation et Récepteurs Matriciels (SiRMa), UMR CNRS/URCA 7369, SFR CAP Santé, Université de Reims Champagne Ardenne, Faculté des Sciences, Reims, France.

Degradation of elastin leads to the production of elastin-derived peptides (EDP), which exhibit several biological effects, such as cell proliferation or protease secretion. Binding of EDP on the elastin receptor complex (ERC) triggers lactosylceramide (LacCer) production and ERK1/2 activation following ERC Neu-1 subunit activation. The ability for ERC to transduce signals is lost during aging, but the mechanism involved is still unknown. In this study, we characterized an in vitro model of aging by subculturing human dermal fibroblasts. This model was used to understand the loss of EDP biological activities during aging. Our results show that ERC uncoupling does not rely on Neu-1 or PPCA mRNA or protein level changes. Furthermore, we observe that the membrane targeting of these subunits is not affected with aging. However, we evidence that Neu-1 activity and LacCer production are altered. Basal Neu-1 catalytic activity is strongly increased in aged cells. Consequently, EDP fail to promote Neu-1 catalytic activity and LacCer production in these cells. In conclusion, we propose, for the first time, an explanation for ERC uncoupling based on the age-related alterations of Neu-1 activity and LacCer production that may explain the loss of EDP-mediated effects occurring during aging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129994PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473072PMC
April 2016

Identification of TAX2 peptide as a new unpredicted anti-cancer agent.

Oncotarget 2015 Jul;6(20):17981-8000

Université de Reims Champagne-Ardenne, Laboratoire SiRMa, UFR Sciences Exactes et Naturelles, Reims, France.

The multi-modular glycoprotein thrombospondin-1 (TSP-1) is considered as a key actor within the tumor microenvironment. Besides, TSP-1 binding to CD47 is widely reported to regulate cardiovascular function as it promotes vasoconstriction and angiogenesis limitation. Therefore, many studies focused on targeting TSP-1:CD47 interaction, aiming for up-regulation of physiological angiogenesis to enhance post-ischemia recovery or to facilitate engraftment. Thus, we sought to identify an innovative selective antagonist for TSP-1:CD47 interaction. Protein-protein docking and molecular dynamics simulations were conducted to design a novel CD47-derived peptide, called TAX2. TAX2 binds TSP-1 to prevent TSP-1:CD47 interaction, as revealed by ELISA and co-immunoprecipitation experiments. Unexpectedly, TAX2 inhibits in vitro and ex vivo angiogenesis features in a TSP-1-dependent manner. Consistently, our data highlighted that TAX2 promotes TSP-1 binding to CD36-containing complexes, leading to disruption of VEGFR2 activation and downstream NO signaling. Such unpredicted results prompted us to investigate TAX2 potential in tumor pathology. A multimodal imaging approach was conducted combining histopathological staining, MVD, MRI analysis and μCT monitoring for tumor angiography longitudinal follow-up and 3D quantification. TAX2 in vivo administrations highly disturb syngeneic melanoma tumor vascularization inducing extensive tumor necrosis and strongly inhibit growth rate and vascularization of human pancreatic carcinoma xenografts in nude mice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627230PMC
http://dx.doi.org/10.18632/oncotarget.4025DOI Listing
July 2015

Saffron extracts alleviate cardiomyocytes injury induced by doxorubicin and ischemia-reperfusion in vitro.

Drug Chem Toxicol 2016 17;39(1):87-96. Epub 2015 Apr 17.

a Physiology Lab , Oxidative Stress and Antioxidant Group, Faculty of Medical Sciences and Doctoral School of Science and Technology, Lebanese University , Hadat , Beirut , Lebanon .

Doxorubicin (DOX), a highly active chemotherapeutic drug, faces limitations in clinical application due to severe cardiotoxic effects (mainly through increased oxidative stress). Therefore, its effect is exacerbated in subjects with ischemic heart disease. We have recently reported that saffron extract (SAF), a natural compound mainly consisting of safranal and corcins, exerts a protective effect against DOX oxidative cytotoxicity in isolated rabbit hearts. Here, we aimed to investigate whether SAF exerts cardioprotection against combined ischemia-reperfusion (I/R) and DOX toxicity in H9c2 cardiomyocytes. H9c2 were subjected to simulated I/R, with or without DOX treatment at reperfusion, in the presence or absence of SAF prior to ischemia or at reperfusion. We evaluated the effects of these treatments by MTT, LDH and western blot analysis. Apoptosis was assessed by Hoechst 33258 staining, tetramethyl rhodamine methyl ester fluorescence and caspase activity. The results showed that I/R and DOX significantly decreased cardiomyocytes viability, inhibited reperfusion injury salvage kinase cardioprotective pathway, reduced contractile proteins (α-Actinine, Troponine C and MLC), increased caspase-3 expression and induced loss of mitochondrial membrane potential. These effects were remarkably inhibited by treatment with SAF (10 μg/mL) at reperfusion. SAF activated AKT/P70S6K and ERK1/2, restored contractile proteins expression, inhibited mitochondrial permeability transition pore and decreased caspase-3 activity. In conclusion, our findings indicate that SAF treatment exerted cardioprotection against I/R and DOX toxicity by reducing oxidative stress (LDH assay). Thereby, SAF offers a potential novel antioxidant therapeutic strategy to counteract I/R and DOX cardiotoxicity, paving the way for future clinical trials.
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http://dx.doi.org/10.3109/01480545.2015.1036281DOI Listing
October 2016

Cardioprotective effect of saffron extracts against acute doxorubicin toxicity in isolated rabbit hearts submitted to ischemia-reperfusion injury.

Z Naturforsch C J Biosci 2014 Nov-Dec;69(11-12):459-70

Doxorubicin (DOX) is an anthracycline antibiotic routinely used as a chemotherapeutic agent for the treatment of solid tumours. However, DOX possesses an acute and cumulative cardiotoxicity due to free radical production. The present study was designed to investigate the possible protective effects of saffron (Crocus sativus) extracts against DOX-induced acute cardiotoxicity in isolated rabbit hearts submitted to 30 min global ischemia followed by 40 min reperfusion. DOX was delivered during reperfusion, without or with saffron given 5 min before ischemia or at reperfusion. Cardiodynamic, biochemical, and histopathological parameters were determined. In addition, to determine the expression of the AKT/mTOR/4EBP1 pathway, the levels of p38 MAPK and cardiac troponin T in heart homogenates were visualized by Western blotting. DOX administration during 40 min of reperfusion increased ischemic tissue damage, but did not act synergistically. Administration of saffron extracts during the first minutes of reperfusion significantly reduced oxidative myocardial damage, but was less effective when given before ischemia. Subsequent Western blot analysis revealed that saffron administration preserved cardiac troponin T proteins, inhibited the p38 MAPK pathway, and activated the AKT/mTOR/4EBP1 pathway in reperfusion- and DOX-treated rabbit hearts. In conclusion, saffron extracts, acting through antioxidant and antiapoptotic mechanisms, exhibited a protective effect against DOX-induced cardiotoxicity under ischemic condition.
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http://dx.doi.org/10.5560/znc.2014-0124DOI Listing
May 2015

Ethoxyfagaronine, a synthetic analogue of fagaronine that inhibits vascular endothelial growth factor-1, as a new anti-angiogeneic agent.

Invest New Drugs 2015 Feb 19;33(1):75-85. Epub 2014 Nov 19.

CNRS UMR7369 MEDyC, Laboratoire SiRMa, SFR CAP-Santé, Université de Reims Champagne-Ardenne, Moulin de la Housse, BP 1039, 51687, Reims cedex 2, France.

Angiogenesis plays a pivotal role in tumorigenesis and also contributes to the pathogenesis of hematologic malignancies. A number of plant compounds have shown efficacy in preclinical and clinical studies and some of them possess an anti-angiogenic activity. Our present findings report anti-angiogenic activities of ethoxyfagaronine (etxfag), a synthetic derivative of fagaronine. Once determined the non-cytotoxic concentration of etxfag, we showed that the drug inhibits VEGF-induced angiogenesis in a Matrigel™ plug assay and suppresses ex vivo sprouting from VEGF-treated aortic rings. Each feature leading to neovascularization was then investigated and results demonstrate that etxfag prevents VEGF-induced migration and tube formation in human umbilical vein endothelial cells (HUVEC). Moreover, etxfag also suppresses VEGF-induced VEGFR-2 phosphorylation and inhibits FAK phosphorylation at Y-861 as well as focal adhesion complex turnover. Beside these effects, etxfag modifies MT1-MMP localization at the endothelial cell membrane. Finally, immunoprecipitation assay revealed that etxfag decreases VEGF binding to VEGFR-2. As we previously reported that etxfag is able to prevent leukemic cell invasiveness and adhesion to fibronectin, all together our data collectively support the anti-angiogenic activities of etxfag which could represent an additional approach to current anti-cancer therapies.
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http://dx.doi.org/10.1007/s10637-014-0184-4DOI Listing
February 2015