Publications by authors named "Cynthia Tannous"

8 Publications

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Insights into the modulation of the interferon response and NAD in the context of COVID-19.

Int Rev Immunol 2021 Aug 11:1-11. Epub 2021 Aug 11.

Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in dramatic worldwide mortality. Along with developing vaccines, the medical profession is exploring new strategies to curb this pandemic. A better understanding of the molecular consequences of SARS-CoV-2 cellular infection could lead to more effective and safer treatments. This review discusses the potential underlying impact of SARS-CoV-2 in modulating interferon (IFN) secretion and in causing mitochondrial NAD depletion that could be directly linked to COVID-19's deadly manifestations. What is known or surmised about an imbalanced innate immune response and mitochondrial dysfunction post-SARS-CoV-2 infection, and the potential benefits of well-timed IFN treatments and NAD boosting therapies in the context of the COVID-19 pandemic are discussed.
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http://dx.doi.org/10.1080/08830185.2021.1961768DOI Listing
August 2021

Transforming iodoquinol into broad spectrum anti-tumor leads: Repurposing to modulate redox homeostasis.

Bioorg Chem 2021 08 31;113:105035. Epub 2021 May 31.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address:

We managed to repurpose the old drug iodoquinol to a series of novel anticancer 7-iodo-quinoline-5,8-diones. Twelve compounds were identified as inhibitors of moderate to high potency on an inhouse MCF-7 cell line, of which 2 compounds (5 and 6) were capable of reducing NAD level in MCF-7 cells in concentrations equivalent to half of their ICs, potentially due to NAD(P)H quinone oxidoreductase (NQO1) inhibition. The same 2 compounds (5 and 6) were capable of reducing p53 expression and increasing reactive oxygen species levels, which further supports the NQO-1 inhibitory activity. Furthermore, 4 compounds (compounds 5-7 and 10) were qualified by the Development Therapeutic Program (DTP) division of the National Cancer Institute (NCI) for full panel five-dose in vitro assay to determine their GI on the 60 cell lines. All five compounds showed broad spectrum sub-micromolar to single digit micromolar GI against a wide range of cell lines. Cell cycle analysis and dual staining assays with annexin V-FITC/propidium iodide on MCF-7 cells confirmed the capability of the most active compound (compound 5) to induce cell cycle arrest at Pre-G1 and G2/M phases as well as apoptosis. Both cell cycle arrest and apoptosis were affirmed at the molecular level by the ability of compound 5 to enhance the expression levels of caspase-3 and Bax together with suppressing that of CDK1 and Bcl-2. Additionally, an anti-angiogenic effect was evident with compound 5 as supported by the decreased expression of VEGF. Interesting binding modes within NQO-1 active site had been identified and confirmed by both molecular docking and dymanic experiments.
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http://dx.doi.org/10.1016/j.bioorg.2021.105035DOI Listing
August 2021

NMRK2 Gene Is Upregulated in Dilated Cardiomyopathy and Required for Cardiac Function and NAD Levels during Aging.

Int J Mol Sci 2021 Mar 29;22(7). Epub 2021 Mar 29.

Inserm Unit UMR-S 1180 CARPAT, Faculty of Pharmacy, Université Paris-Saclay, 92296 Châtenay-Malabry, France.

Dilated cardiomyopathy (DCM) is a disease of multifactorial etiologies, the risk of which is increased by male sex and age. There are few therapeutic options for patients with DCM who would benefit from identification of common targetable pathways. We used bioinformatics to identify the gene involved in nicotinamide adenine dinucleotde (NAD) coenzyme biosynthesis as activated in different mouse models and in hearts of human patients with DCM while the gene controlling a parallel pathway is repressed. A short NMRK2 protein isoform is also known as muscle integrin binding protein (MIBP) binding the α7β1 integrin complex. We investigated the cardiac phenotype of Nmrk2-KO mice to establish its role in cardiac remodeling and function. Young Nmrk2-KO mice developed an eccentric type of cardiac hypertrophy in response to pressure overload rather than the concentric hypertrophy observed in controls. mice developed a progressive DCM-like phenotype with aging, associating eccentric remodeling of the left ventricle and a decline in ejection fraction and showed a reduction in myocardial NAD levels at 24 months. In agreement with involvement of NMRK2 in integrin signaling, we observed a defect in laminin deposition in the basal lamina of cardiomyocytes leading to increased fibrosis at middle age. The was repressed at both transcript and protein level at 24 months. gene is required to preserve cardiac structure and function, and becomes an important component of the NAD biosynthetic pathways during aging. Molecular characterization of compounds modulating this pathway may have therapeutic potential.
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http://dx.doi.org/10.3390/ijms22073534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036583PMC
March 2021

Nicotinamide adenine dinucleotide: Biosynthesis, consumption and therapeutic role in cardiac diseases.

Acta Physiol (Oxf) 2021 03 21;231(3):e13551. Epub 2020 Sep 21.

Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

Nicotinamide adenine dinucleotide (NAD) is an abundant cofactor that plays crucial roles in several cellular processes. NAD can be synthesized de novo starting with tryptophan, or from salvage pathways starting with NAD precursors like nicotinic acid (NA), nicotinamide (NAM) or nicotinamide riboside (NR), referred to as niacin/B vitamins, arising from dietary supply or from cellular NAD catabolism. Given the interconversion between its oxidized (NAD ) and reduced form (NADH), NAD participates in a wide range of reactions: regulation of cellular redox status, energy metabolism and mitochondrial biogenesis. Plus, NAD acts as a signalling molecule, being a cosubstrate for several enzymes such as sirtuins, poly-ADP-ribose-polymerases (PARPs) and some ectoenzymes like CD38, regulating critical biological processes like gene expression, DNA repair, calcium signalling and circadian rhythms. Given the large number of mitochondria present in cardiac tissue, the heart has the highest NAD levels and is one of the most metabolically demanding organs. In several models of heart failure, myocardial NAD levels are depressed and this depression is caused by mitochondrial dysfunction, metabolic remodelling and inflammation. Emerging evidence suggests that regulating NAD homeostasis by NAD precursor supplementation has therapeutic efficiency in improving myocardial bioenergetics and function. This review provides an overview of the latest understanding of the different NAD biosynthesis pathways, as well as its role as a signalling molecule particularly in cardiac tissue. We highlight the significance of preserving NAD equilibrium in various models of heart diseases and shed light on the potential pharmacological interventions aiming to use NAD boosters as therapeutic agents.
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http://dx.doi.org/10.1111/apha.13551DOI Listing
March 2021

Sex-based differences in myocardial infarction-induced kidney damage following cigarette smoking exposure: more renal protection in premenopausal female mice.

Biosci Rep 2020 06;40(6)

Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon.

The impact of cigarette smoking (CS) on kidney homeostasis in the presence of myocardial infarction (MI) in both males and females remains poorly elucidated. C57BL6/J mice were exposed to 2 weeks of CS prior to MI induction followed by 1 week of CS exposure in order to investigate the impact of CS on kidney damage in the presence of MI. Cardiac hemodynamic analysis revealed a significant decrease in ejection fraction (EF) in CS-exposed MI male mice when compared with the relative female subjects, whereas cardiac output (CO) comparably decreased in CS-exposed MI mice of both sexes. Kidney structural alterations, including glomerular retraction, proximal convoluted tubule (PCT) cross-sectional area, and total renal fibrosis were more pronounced in CS-exposed MI male mice when compared with the relative female group. Although renal reactive oxygen species (ROS) generation and glomerular DNA fragmentation significantly increased to the same extent in CS-exposed MI mice of both sexes, alpha-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF) significantly increased in CS-exposed MI male mice, only. Metabolically, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide riboside-1 (NMRK-1) substantially increased in CS-exposed MI female mice only, whereas sirtuin (SIRT)-1 and SIRT-3 substantially decreased in CS-exposed MI male mice compared with their relative female group. Additionally, renal NAD levels significantly decreased only in CS-exposed MI male mice. In conclusion, MI female mice exhibited pronounced renal protection following CS when compared with the relative male groups.
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http://dx.doi.org/10.1042/BSR20193229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313446PMC
June 2020

IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture.

Clin Sci (Lond) 2020 06;134(11):1191-1218

Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon.

Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 μg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.
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http://dx.doi.org/10.1042/CS20200402DOI Listing
June 2020

Aged Nicotinamide Riboside Kinase 2 Deficient Mice Present an Altered Response to Endurance Exercise Training.

Front Physiol 2018 19;9:1290. Epub 2018 Sep 19.

Signalling and Cardiovascular Pathophysiology-UMR-S 1180, Univ. Paris-Sud, INSERM, Université Paris-Saclay, Châtenay-Malabry, France.

Skeletal muscle aging is marked by the development of a sarcopenic phenotype, a global decline of muscle energetic capacities, and an intolerance to exercise. Among the metabolic disorders involved in this syndrome, NAD metabolism was shown to be altered in skeletalmuscle, with an important role for the NAMPT enzyme recycling the nicotinamide precursor. An alternative pathway for NAD biosynthesis has been described for the nicotinamide riboside vitamin B3 precursor used by the NMRK kinases, including the striated muscle-specific NMRK2. With this study, our goal is to explore the ability of 16-month-old mice to perform endurance exercise and study the consequences on muscle adaptation to exercise. 10 control and 6 mice were used and randomly assigned to sedentary and treadmill endurance training groups. After 9 weeks of training, heart and skeletal muscle samples were harvested and used for gene expression analysis, NAD levels measurements and immunohistochemistry staining. Endurance training triggered a reduction in the expression of Cpt1b and AcadL genes involved in fatty acid catabolism in the heart of mice, not in control mice. NAD levels were not altered in heart or skeletal muscle, nor at baseline neither after exercise training in any group. gene encoding for the slow MHC-I was more strongly induced by exercise in mice than in controls. Moreover, -15 expression levels is higher in mice skeletal muscle at baseline compared to controls. No fiber type switch was observed in plantaris after exercise, but fast fibers diameter was reduced in aged control mice, not in mice. No fiber type switch or diameter modification was observed in soleus muscle. In this study, we demonstrated for the first time a phenotype in old mice in response to endurance exercise training. Although NMRK2 seems to be predominantly dispensable to maintain global NAD levels in heart and skeletal muscle, we demonstrated a maladaptive metabolic response to exercise in cardiac and skeletal muscle, showing that NMRK2 has a specific and restricted role in NAD signaling compared to the NAMPT pathway.
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http://dx.doi.org/10.3389/fphys.2018.01290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156423PMC
September 2018

Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy.

Circulation 2018 05 7;137(21):2256-2273. Epub 2017 Dec 7.

Signalling and Cardiovascular Pathophysiology, UMR-S 1180, University Paris-Sud, INSERM, Université Paris- Saclay, Châtenay-Malabry, France (C.T., R.D., J.P., M.G., B.M., M.B., A. Garnier, M.M.).

Background: Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD) is emerging as a metabolic target in a number of diseases including heart failure. Little is known on the mechanisms regulating homeostasis of NAD in the failing heart.

Methods: To explore possible alterations of NAD homeostasis in the failing heart, we quantified the expression of NAD biosynthetic enzymes in the human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by Serum Response Factor transcription factor depletion in the heart (SRF) or of cardiac hypertrophy triggered by transverse aorta constriction. We studied the impact of NAD precursor supplementation on cardiac function in both mouse models.

Results: We observed a 30% loss in levels of NAD in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls. We show that the gene is an AMP-activated protein kinase and peroxisome proliferator-activated receptor α responsive gene that is activated by energy stress and NAD depletion in isolated rat cardiomyocytes. Nicotinamide riboside efficiently rescues NAD synthesis in response to FK866-mediated inhibition of nicotinamide phosphoribosyltransferase and stimulates glycolysis in cardiomyocytes. Accordingly, we show that nicotinamide riboside supplementation in food attenuates the development of heart failure in mice, more robustly in DCM, and partially after transverse aorta constriction, by stabilizing myocardial NAD levels in the failing heart. Nicotinamide riboside treatment also robustly increases the myocardial levels of 3 metabolites, nicotinic acid adenine dinucleotide, methylnicotinamide, and N1-methyl-4-pyridone-5-carboxamide, that can be used as validation biomarkers for the treatment.

Conclusions: The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954688PMC
May 2018
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