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

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 (SRFHKO) 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 Nmrk2 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.

Microsecond and nanosecond electric pulses in cancer treatments.

New local treatments based on electromagnetic fields have been developed as non-surgical and minimally invasive treatments of tumors. In particular, short electric pulses can induce important non-thermal changes in cell physiology, especially the permeabilization of the cell membrane. The aim of this review is to summarize the present data on the electroporation-based techniques: electrochemotherapy (ECT), nanosecond pulsed electric fields (nsPEFs), and irreversible electroporation (IRE). ECT is a safe, easy, and efficient technique for the treatment of solid tumors that uses cell-permeabilizing electrical pulses to enhance the activity of a non-permeant (bleomycin) or low permeant (cisplatin) anticancer drug with a very high intrinsic cytotoxicity. The most interesting feature of ECT is its unique ability to selectively kill tumor cells without harming normal surrounding tissue. ECT is already used widely in the clinics in Europe. nsPEFs could represent a drug free, purely electrical cancer therapy. They allow the inhibition of tumor growth, and interestingly, nsPEF can target intracellular organelles. However, many questions remain on the mechanism of action of these pulses. Finally, IRE is a new ablation procedure using pulses that provoke the permanent permeabilization of the cells resulting in their death. This technique does not result in any thermal effect, which is its main advantage in current physical ablation technologies. For both the nsPEF and the IRE, the preservation of the normal tissue, which is characteristic of ECT, has not yet been shown and their safety and efficacy still have to be investigated thoroughly in vivo and in the clinics.

Relationship between climate, pollen concentrations of Ambrosia and medical consultations for allergic rhinitis in Montreal, 1994-2002.

The aim of this study is to evaluate the influence of meteorological factors on Ambrosia pollen concentrations and its impact on medical consultations for allergic rhinitis of residents from various socio-economic levels in Montréal (Québec, Canada) between 1994 and 2002. The study was conducted to recognize the sensitivity of pollen productivity to daily climate variability in order to estimate the consequences on human health vulnerability in the context of global climate change. Information related to medical consultations for allergic rhinitis due to pollen comes from the Quebec Health Insurance Board (Régie de l'assurance-maladie du Québec). Ambrosia pollen concentration was measured by the Aerobiology Research Laboratories (Nepean, Ontario). Daily temperature (maximum, minimum, and mean) and precipitation data were obtained from the Meteorological Service of Canada. Socio-economic data come from the 1996 and 2001 census data of Statistics Canada. Between 1994 and 2002, during the Ambrosia pollen season, 7667 consultations for allergic rhinitis due to pollen were recorded. We found a significant association between the number of medical consultations and pollen levels. Significant associations were detected for over-consultation the day of exposure, 1, 2, 3 and 5 days after exposure to high levels of pollen. The consultation rate is higher from low-income residents (3.10 consultations per 10,000 inhabitants) than for high-income (1.65 consultations per 10,000 inhabitants). Considering the demonstrated impact of pollen levels on health, it has become critical to ensure adequate monitoring of Ambrosia and its meteorological sensivity in the context of the anticipated climate change and its potential consequences on human health.