Therapeutic potential of emerging NAD+-increasing strategies for cardiovascular diseases

Altres ajuts: Fundació La Marató de TV3 (303/C/2016)(201602.30.31)Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases

Global application of an unoccupied aerial vehicle photogrammetry protocol for predicting aboveground biomass in non‐forest ecosystems

P. 1-15Non-forest ecosystems, dominated by shrubs, grasses and herbaceous plants, provide ecosystem services including carbon sequestration and forage for grazing, and are highly sensitive to climatic changes. Yet these ecosystems are poorly represented in remotely sensed biomass products and are undersampled by in situ monitoring. Current global change threats emphasize the need for new tools to capture biomass change in non-forest ecosystems at appropriate scales. Here we developed and deployed a new protocol for photogrammetric height using unoccupied aerial vehicle (UAV) images to test its capability for delivering standardized measurements of biomass across a globally distributed field experiment. We assessed whether canopy height inferred from UAV photogrammetry allows the prediction of aboveground biomass (AGB) across low-stature plant species by conducting 38 photogrammetric surveys over 741 harvested plots to sample 50 species. We found mean canopy height was strongly predictive of AGB across species, with a median adjusted R2 of 0.87 (ranging from 0.46 to 0.99) and median prediction error from leave-one-out cross-validation of 3.9%. Biomass per-unit-of-height was similar within but different among, plant functional types. We found that photogrammetric reconstructions of canopy height were sensitive to wind speed but not sun elevation during surveys. We demonstrated that our photogrammetric approach produced generalizable measurements across growth forms and environmental settings and yielded accuracies as good as those obtained from in situ approaches. We demonstrate that using a standardized approach for UAV photogrammetry can deliver accurate AGB estimates across a wide range of dynamic and heterogeneous ecosystems. Many academic and land management institutions have the technical capacity to deploy these approaches over extents of 1–10 ha−1. Photogrammetric approaches could provide much-needed information required to calibrate and validate the vegetation models and satellite-derived biomass products that are essential to understand vulnerable and understudied non-forested ecosystems around the globe.S

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Nicotinamide Prevents Apolipoprotein B-Containing Lipoprotein Oxidation, Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice

The potential of nicotinamide (NAM) to prevent atherosclerosis has not yet been examined. This study investigated the effect of NAM supplementation on the development of atherosclerosis in a mouse model of the disease. The development of aortic atherosclerosis was significantly reduced (NAM low dose: 45%; NAM high dose: 55%) in NAM-treated, apolipoprotein (Apo)E-deficient mice challenged with a Western diet for 4 weeks. NAM administration significantly increased (1.8-fold) the plasma concentration of proatherogenic ApoB-containing lipoproteins in NAM high-dose (HD)-treated mice compared with untreated mice. However, isolated ApoB-containing lipoproteins from NAM HD mice were less prone to oxidation than those of untreated mice. This result was consistent with the decreased (1.5-fold) concentration of oxidized low-density lipoproteins in this group. Immunohistochemical staining of aortas from NAM-treated mice showed significantly increased levels of IL-10 (NAM low-dose (LD): 1.3-fold; NAM HD: 1.2-fold), concomitant with a significant decrease in the relative expression of TNFα (NAM LD: −44%; NAM HD: −57%). An improved anti-inflammatory pattern was reproduced in macrophages cultured in the presence of NAM. Thus, dietary NAM supplementation in ApoE-deficient mice prevented the development of atherosclerosis and improved protection against ApoB-containing lipoprotein oxidation and aortic inflammation

Nicotinamide effects on adiposity, energy metabolism, inflammation and atherosclerosis in mice

Antecedentes e hipótesis La disfunción del tejido adiposo se encuentra frecuentemente asociada con alteraciones en la homeostasis metabólica, cardiovascular e inflamatoria crónica leve de la obesidad. El tejido adiposo es considerado como diana terapéutica para prevenir la obesidad. Precursores de la nicotinamida adenina dinucleotido (NAD)+, tales como el ribósido de nicotinamida y mononucleótido de nicotinamida promueven el metabolismo energético y previenen la ganancia de peso corporal en modelos animales. Sin embargo, en estos trabajos no se abordó directamente su posible efecto sobre las alteraciones fisiológicas y plásticas del tejido adiposo blanco (TAB). Su posible potencial contra la inflamación crónica, cuyo desarrollo se encuentra frecuentemente ligado al de obesidad, tampoco ha sido evaluado. La nicotinamida (NAM) es otro precursor fisiológico de NAD+. No obstante, su posible contribución sobre este fenotipo está aun pendiente. Por otro lado, aunque su acción anti-oxidante y anti-inflamatoria ya ha sido descrita, su posible contribución en la prevención de arteriosclerosis tampoco ha sido demostrada. Objetivos El objetivo principal de este estudio fue doble: investigar el efecto de la administración de una dosis bien tolerada de NAM sobre [1] la prevención de la ganancia de peso corporal y adiposidad, y [2] la mejora de inflamación crónica en modelos murinos de obesidad inducida por una dieta rica en grasas (DIO, del inglés ‘diet-induced obesity’) y arteriosclerosis (i.e., ratones deficientes en ApoE). Resultados La administración de NAM a animales se realizó a través del agua de bebida ad libitum. El agua suplementada con NAM fue bien tolerada y segura a una dosis inferior a 1%. La suplementación con NAM, a la dosis más alta empleada (1%), previno la ganancia de peso corporal, siendo esto último principalmente atribuido a una disminución en la acumulación de grasa y esteatosis hepática. Ello fue principalmente debido a un [i] aumento en el gasto energético global, [ii] desarrollo de ‘browning’ en TAB subcutáneo (TABsc) a juzgar por un aumento en los niveles tisulares de proteína desacopladora Ucp1, e [iii] inducción de la síntesis de novo de NAD+ y aumento de la relación NAD+/NADH en TABsc. El contenido de AMP en TABsc se encontró significativamente elevado en ratones obesos tratados. Además, la relación NAD+/NADH se encontró directamente relacionada con la relación AMP/ATP, posiblemente sugiriendo una situación de demanda energética aumentada en dicho tejido. Consistentemente, se observó un aumento en la abundancia relativa de la forma activa (fosforilada) de la quinasa activada por AMP (AMPK) en dicho tejido. La suplementación con NAM también mejoró el estado inflamatorio global y previno contra el desarrollo de arteriosclerosis en ratones. Ello se acompañó por elevaciones [i] en las concentraciones circulantes de interleuquina (IL-)10 y [ii] niveles relativos de mRNA de Il10 en tejido adiposo epididimal (TABe) y aórtico, sugiriendo un cambio favorable del fenotipo de macrófagos a uno anti-inflamatorio (macrófagos M2). Esto último se observó asociado con una disminución en el desarrollo de arteriosclerosis en ratones deficientes en ApoE. También se investigó su posible efecto anti-oxidante sistémico y en tejidos diana. Las lipoproteínas circulantes no-HDL de ratones deficientes de ApoE tratados con NAM presentaron menor susceptibilidad a la oxidación que las de los no tratados, siendo este efecto debido al menos en parte a la acción antioxidante intrínseca por parte de NAM. Conclusiones La suplementación dietética de NAM previno la ganancia de peso corporal y adiposidad a través de la estimulación del gasto energético en ratones. Ello se acompañó de una inducción de ‘browning’ y aumento de demanda energética en TAB. NAM también promovió acciones anti-inflamatoria y anti-oxidante. Su administración aumentó la expression génica de Il10 en tejidos diana, incluyendo la aorta, y protegió contra el desarrollo de arteriosclerosis.Background and hypothesis Adipose tissue dysfunction is a hallmark of obesity and is frequently associated with distorted metabolic homeostasis, cardiovascular and chronic, low-grade inflammatory diseases. Several recent studies point to pharmacological and/or nutritional health initiatives targeting adipose tissue being a promising approach to obesity prevention. In this regard, nicotinamide adenine dinucleotide (NAD)+ precursors, such as nicotinamide riboside and mononucleotide nicotinamide has been proven beneficial in increasing energy metabolism and preventing body weight gain in vivo. However, neither their favorable anti-obesity impact on disturbed white adipose tissue (WAT) physiology and plasticity nor in alleviating chronic inflammation, which frequently accompanies obesity, was not eventually pursued in any of these studies. In addition to the above-mentioned NAD precursors, nicotinamide (NAM) is also a physiological precursor of NAD+. However, its contribution in boosting energy metabolism and body weight gain still remains elusive. Although a growing body of evidences also supports a role for NAM as an anti-oxidant and anti-inflammatory agent both in vitro and in vivo, its potential contribution in preventing atherosclerosis, which is one of the main mechanisms involved in cardiovascular disease in vivo, has not previously been proven yet. Aims The aim of this study was twofold: to investigate the effect of NAM supplementation in (1) preventing weight gain and adiposity; (2) improving features of chronic inflammation in appropriate mouse models of obesity (diet-induced obesity -DIO- mice) and atherosclerosis (i.e., ApoE-deficient mice). Results NAM administration to mice was provided orally via tap water at libitum. Its administration was shown palatable, safe and well tolerated at doses below 1%. NAM supplementation, at the highest dose used (1%) (NAM HD-treated mice), prevented body weight gain, with the latter being mainly and repeatedly accompanied by reduction in fat accumulation in different regional depots, and hepatic steatosis. Mechanistically, such anti-adiposity effect by NAM was mainly accompanied by an [i] increased global energy expenditure, [ii] enhanced promotion of browning in subcutaneous (sc)WAT, as revealed by elevations in the relative mRNA and protein abundance of the uncoupling protein (Ucp)-1, and [iii] elevation of the de novo synthesis of NAD+ and NAD/NADH ratio in scWAT of NAM HD-treated, DIO mice. Notably, the AMP content was significantly elevated in scWAT of NAM HD-treated, DIO mice. Also, the NAD+/NADH ratio was directly related to the AMP/ATP ratio. Overall these data suggested a situation of energy demand in scWAT from NAM HD-treated mice. Concomitantly, the protein abundance of the active (phosphorylated) form of AMP-activated kinase was also elevated in this tissue of NAM HD-treated mice. NAM supplementation also improved the global inflammatory condition and prevented atherosclerosis development in mice. This was revealed by [i] elevations in the circulating concentrations of interleukin (IL-)10 and [ii] up-regulation of relative mRNA of Il10 in both adipose and aortic tissues, which potentially suggested a switch to anti-inflammatory M2 macrophages. This phenotype was accompanied by a commensurate reduction in atherosclerosis development in NAM-treated, ApoE-deficient mice. In addition to improved inflammation, non-HDL of NAM-treated, ApoE-deficient mice were less prone to oxidation than those from untreated mice, being this effect at least partly provided by the intrinsic anti-oxidant action of NAM. Conclusions Dietary supplementation with NAM to mice prevented body weight gain and adiposity by boosting energy expenditure, with this being mainly attributed to induction of browning and energy demand in scWAT. NAM also promoted anti-inflammatory and anti-oxidant actions. Its administration increased gene expression Il10 in target tissues, including aorta, and protected against development of atherosclerosis

Nicotinamide effects on adiposity, energy metabolism, inflammation and atherosclerosis in mice /

Departament responsable de la tesi: Departament de Bioquímica i Biologia Molecular.Antecedentes e hipótesisLa disfunción del tejido adiposo se encuentra frecuentemente asociada con alteraciones en la homeostasis metabólica, cardiovascular e inflamatoria crónica leve de la obesidad. El tejido adiposo es considerado como diana terapéutica para prevenir la obesidad. Precursores de la nicotinamida adenina dinucleotido (NAD)+, tales como el ribósido de nicotinamida y mononucleótido de nicotinamida promueven el metabolismo energético y previenen la ganancia de peso corporal en modelos animales. Sin embargo, en estos trabajos no se abordó directamente su posible efecto sobre las alteraciones fisiológicas y plásticas del tejido adiposo blanco (TAB). Su posible potencial contra la inflamación crónica, cuyo desarrollo se encuentra frecuentemente ligado al de obesidad, tampoco ha sido evaluado. La nicotinamida (NAM) es otro precursor fisiológico de NAD+. No obstante, su posible contribución sobre este fenotipo está aun pendiente. Por otro lado, aunque su acción anti-oxidante y anti-inflamatoria ya ha sido descrita, su posible contribución en la prevención de arteriosclerosis tampoco ha sido demostrada.ObjetivosEl objetivo principal de este estudio fue doble: investigar el efecto de la administración de una dosis bien tolerada de NAM sobre [1] la prevención de la ganancia de peso corporal y adiposidad, y [2] la mejora de inflamación crónica en modelos murinos de obesidad inducida por una dieta rica en grasas (DIO, del inglés 'diet-induced obesity') y arteriosclerosis (i.e., ratones deficientes en ApoE).ResultadosLa administración de NAM a animales se realizó a través del agua de bebida ad libitum. El agua suplementada con NAM fue bien tolerada y segura a una dosis inferior a 1%.La suplementación con NAM, a la dosis más alta empleada (1%), previno la ganancia de peso corporal, siendo esto último principalmente atribuido a una disminución en la acumulación de grasa y esteatosis hepática. Ello fue principalmente debido a un [i] aumento en el gasto energético global, [ii] desarrollo de 'browning' en TAB subcutáneo (TABsc) a juzgar por un aumento en los niveles tisulares de proteína desacopladora Ucp1, e [iii] inducción de la síntesis de novo de NAD+ y aumento de la relación NAD+/NADH en TABsc. El contenido de AMP en TABsc se encontró significativamente elevado en ratones obesos tratados. Además, la relación NAD+/NADH se encontró directamente relacionada con la relación AMP/ATP, posiblemente sugiriendo una situación de demanda energética aumentada en dicho tejido. Consistentemente, se observó un aumento en la abundancia relativa de la forma activa (fosforilada) de la quinasa activada por AMP (AMPK) en dicho tejido.La suplementación con NAM también mejoró el estado inflamatorio global y previno contra el desarrollo de arteriosclerosis en ratones. Ello se acompañó por elevaciones [i] en las concentraciones circulantes de interleuquina (IL-)10 y [ii] niveles relativos de mRNA de Il10 en tejido adiposo epididimal (TABe) y aórtico, sugiriendo un cambio favorable del fenotipo de macrófagos a uno anti-inflamatorio (macrófagos M2). Esto último se observó asociado con una disminución en el desarrollo de arteriosclerosis en ratones deficientes en ApoE. También se investigó su posible efecto anti-oxidante sistémico y en tejidos diana. Las lipoproteínas circulantes no-HDL de ratones deficientes de ApoE tratados con NAM presentaron menor susceptibilidad a la oxidación que las de los no tratados, siendo este efecto debido al menos en parte a la acción antioxidante intrínseca por parte de NAM. ConclusionesLa suplementación dietética de NAM previno la ganancia de peso corporal y adiposidad a través de la estimulación del gasto energético en ratones. Ello se acompañó de una inducción de 'browning' y aumento de demanda energética en TAB. NAM también promovió acciones anti-inflamatoria y anti-oxidante. Su administración aumentó la expression génica de Il10 en tejidos diana, incluyendo la aorta, y protegió contra el desarrollo de arteriosclerosis.Antecedentes e hipótesis La disfunción del tejido adiposo se encuentra frecuentemente asociada con alteraciones en la homeostasis metabólica, cardiovascular e inflamatoria crónica leve de la obesidad. El tejido adiposo es considerado como diana terapéutica para prevenir la obesidad. Precursores de la nicotinamida adenina dinucleotido (NAD)+, tales como el ribósido de nicotinamida y mononucleótido de nicotinamida promueven el metabolismo energético y previenen la ganancia de peso corporal en modelos animales. Sin embargo, en estos trabajos no se abordó directamente su posible efecto sobre las alteraciones fisiológicas y plásticas del tejido adiposo blanco (TAB). Su posible potencial contra la inflamación crónica, cuyo desarrollo se encuentra frecuentemente ligado al de obesidad, tampoco ha sido evaluado. La nicotinamida (NAM) es otro precursor fisiológico de NAD+. No obstante, su posible contribución sobre este fenotipo está aun pendiente. Por otro lado, aunque su acción anti-oxidante y anti-inflamatoria ya ha sido descrita, su posible contribución en la prevención de arteriosclerosis tampoco ha sido demostrada. Objetivos El objetivo principal de este estudio fue doble: investigar el efecto de la administración de una dosis bien tolerada de NAM sobre [1] la prevención de la ganancia de peso corporal y adiposidad, y [2] la mejora de inflamación crónica en modelos murinos de obesidad inducida por una dieta rica en grasas (DIO, del inglés 'diet-induced obesity') y arteriosclerosis (i.e., ratones deficientes en ApoE). Resultados La administración de NAM a animales se realizó a través del agua de bebida ad libitum. El agua suplementada con NAM fue bien tolerada y segura a una dosis inferior a 1%. La suplementación con NAM, a la dosis más alta empleada (1%), previno la ganancia de peso corporal, siendo esto último principalmente atribuido a una disminución en la acumulación de grasa y esteatosis hepática. Ello fue principalmente debido a un [i] aumento en el gasto energético global, [ii] desarrollo de 'browning' en TAB subcutáneo (TABsc) a juzgar por un aumento en los niveles tisulares de proteína desacopladora Ucp1, e [iii] inducción de la síntesis de novo de NAD+ y aumento de la relación NAD+/NADH en TABsc. El contenido de AMP en TABsc se encontró significativamente elevado en ratones obesos tratados. Además, la relación NAD+/NADH se encontró directamente relacionada con la relación AMP/ATP, posiblemente sugiriendo una situación de demanda energética aumentada en dicho tejido. Consistentemente, se observó un aumento en la abundancia relativa de la forma activa (fosforilada) de la quinasa activada por AMP (AMPK) en dicho tejido. La suplementación con NAM también mejoró el estado inflamatorio global y previno contra el desarrollo de arteriosclerosis en ratones. Ello se acompañó por elevaciones [i] en las concentraciones circulantes de interleuquina (IL-)10 y [ii] niveles relativos de mRNA de Il10 en tejido adiposo epididimal (TABe) y aórtico, sugiriendo un cambio favorable del fenotipo de macrófagos a uno anti-inflamatorio (macrófagos M2). Esto último se observó asociado con una disminución en el desarrollo de arteriosclerosis en ratones deficientes en ApoE. También se investigó su posible efecto anti-oxidante sistémico y en tejidos diana. Las lipoproteínas circulantes no-HDL de ratones deficientes de ApoE tratados con NAM presentaron menor susceptibilidad a la oxidación que las de los no tratados, siendo este efecto debido al menos en parte a la acción antioxidante intrínseca por parte de NAM. Conclusiones La suplementación dietética de NAM previno la ganancia de peso corporal y adiposidad a través de la estimulación del gasto energético en ratones. Ello se acompañó de una inducción de 'browning' y aumento de demanda energética en TAB. NAM también promovió acciones anti-inflamatoria y anti-oxidante. Su administración aumentó la expression génica de Il10 en tejidos diana, incluyendo la aorta, y protegió contra el desarrollo de arteriosclerosis.Background and hypothesis Adipose tissue dysfunction is a hallmark of obesity and is frequently associated with distorted metabolic homeostasis, cardiovascular and chronic, low-grade inflammatory diseases. Several recent studies point to pharmacological and/or nutritional health initiatives targeting adipose tissue being a promising approach to obesity prevention. In this regard, nicotinamide adenine dinucleotide (NAD)+ precursors, such as nicotinamide riboside and mononucleotide nicotinamide has been proven beneficial in increasing energy metabolism and preventing body weight gain in vivo. However, neither their favorable anti-obesity impact on disturbed white adipose tissue (WAT) physiology and plasticity nor in alleviating chronic inflammation, which frequently accompanies obesity, was not eventually pursued in any of these studies. In addition to the above-mentioned NAD precursors, nicotinamide (NAM) is also a physiological precursor of NAD+. However, its contribution in boosting energy metabolism and body weight gain still remains elusive. Although a growing body of evidences also supports a role for NAM as an anti-oxidant and anti-inflammatory agent both in vitro and in vivo, its potential contribution in preventing atherosclerosis, which is one of the main mechanisms involved in cardiovascular disease in vivo, has not previously been proven yet. Aims The aim of this study was twofold: to investigate the effect of NAM supplementation in (1) preventing weight gain and adiposity; (2) improving features of chronic inflammation in appropriate mouse models of obesity (diet-induced obesity -DIO- mice) and atherosclerosis (i.e., ApoE-deficient mice). Results NAM administration to mice was provided orally via tap water at libitum. Its administration was shown palatable, safe and well tolerated at doses below 1%. NAM supplementation, at the highest dose used (1%) (NAM HD-treated mice), prevented body weight gain, with the latter being mainly and repeatedly accompanied by reduction in fat accumulation in different regional depots, and hepatic steatosis. Mechanistically, such anti-adiposity effect by NAM was mainly accompanied by an [i] increased global energy expenditure, [ii] enhanced promotion of browning in subcutaneous (sc)WAT, as revealed by elevations in the relative mRNA and protein abundance of the uncoupling protein (Ucp)-1, and [iii] elevation of the de novo synthesis of NAD+ and NAD/NADH ratio in scWAT of NAM HD-treated, DIO mice. Notably, the AMP content was significantly elevated in scWAT of NAM HD-treated, DIO mice. Also, the NAD+/NADH ratio was directly related to the AMP/ATP ratio. Overall these data suggested a situation of energy demand in scWAT from NAM HD-treated mice. Concomitantly, the protein abundance of the active (phosphorylated) form of AMP-activated kinase was also elevated in this tissue of NAM HD-treated mice. NAM supplementation also improved the global inflammatory condition and prevented atherosclerosis development in mice. This was revealed by [i] elevations in the circulating concentrations of interleukin (IL-)10 and [ii] up-regulation of relative mRNA of Il10 in both adipose and aortic tissues, which potentially suggested a switch to anti-inflammatory M2 macrophages. This phenotype was accompanied by a commensurate reduction in atherosclerosis development in NAM-treated, ApoE-deficient mice. In addition to improved inflammation, non-HDL of NAM-treated, ApoE-deficient mice were less prone to oxidation than those from untreated mice, being this effect at least partly provided by the intrinsic anti-oxidant action of NAM. Conclusions Dietary supplementation with NAM to mice prevented body weight gain and adiposity by boosting energy expenditure, with this being mainly attributed to induction of browning and energy demand in scWAT. NAM also promoted anti-inflammatory and anti-oxidant actions. Its administration increased gene expression Il10 in target tissues, including aorta, and protected against development of atherosclerosis

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases

Altres ajuts: Fundació La Marató de TV3 2015 (20152431) (to F. B.-V.) and 2016 (201602.30.31) (to N.A. and J.J.).Sphingolipids are key signaling molecules involved in the regulation of cell physiology. These species are found in tissues and in circulation. Although they only constitute a small fraction in lipid composition of circulating lipoproteins, their concentration in plasma and distribution among plasma lipoproteins appears distorted under adverse cardiometabolic conditions such as diabetes mellitus. Sphingosine-1-phosphate (S1P), one of their main representatives, is involved in regulating cardiomyocyte homeostasis in different models of experimental cardiomyopathy. Cardiomyopathy is a common complication of diabetes mellitus and represents a main risk factor for heart failure. Notably, plasma concentration of S1P, particularly high-density lipoprotein (HDL)-bound S1P, may be decreased in patients with diabetes mellitus, and hence, inversely related to cardiac alterations. Despite this, little attention has been given to the circulating levels of either total S1P or HDL-bound S1P as potential biomarkers of diabetic cardiomyopathy. Thus, this review will focus on the potential role of HDL-bound S1P as a circulating biomarker in the diagnosis of main cardiometabolic complications frequently associated with systemic metabolic syndromes with impaired insulin signaling. Given the bioactive nature of these molecules, we also evaluated its potential of HDL-bound S1P-raising strategies for the treatment of cardiometabolic disease

Hepatic CD36 downregulation parallels steatosis improvement in morbidly obese undergoing bariatric surgery

[Background] The notion that hepatic expression of genes involved in lipid metabolism is altered in obese patients is relatively new and its relationship with hepatic steatosis and cardiometabolic alterations remains unclear. [Objective] We assessed the impact of Roux-en-Y gastric bypass surgery (RYGB) on the expression profile of genes related to metabolic syndrome in liver biopsies from morbidly obese individuals using a custom-made, focused cDNA microarray, and assessed the relationship between the expression profile and hepatic steatosis regression. [Materials and methods] Plasma and liver samples were obtained from patients at baseline and 12 months after surgery. Samples were assayed for chemical and gene expression analyses, as appropriate. Gene expression profiles were assessed using custom-made, focused TaqMan low-density array cards. [Results] RYGB-induced weight loss produced a favorable reduction in fat deposits, insulin resistance (estimated by homeostasis model assessment of insulin resistance (HOMA-IR)), and plasma and hepatic lipid levels. Compared with the baseline values, the gene expression levels of key targets of lipid metabolism were significantly altered: CD36 was significantly downregulated (−40%; P=0.001), whereas APOB (+27%; P=0.032) and SCARB1 (+37%; P=0.040) were upregulated in response to surgery-induced weight reduction. We also observed a favorable reduction in the expression of the PAI1 gene (−80%; P=0.007) and a significant increase in the expression of the PPARA (+60%; P=0.014) and PPARGC1 genes (+36%; P=0.015). Notably, the relative fold decrease in the expression of the CD36 gene was directly associated with a concomitant reduction in the cholesterol (Spearman’s r=0.92; P=0.001) and phospholipid (Spearman’s r=0.76; P=0.04) contents in this tissue. [Conclusions] For the first time, RYGB-induced weight loss was shown to promote a favorable downregulation of CD36 expression, which was proportional to a favorable reduction in the hepatic cholesterol and phospholipid contents in our morbidly obese subjects following surgery.This work was funded by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (ISCIII) FIS grants CP13/00070 (to JJ) and PI11/01159 and PI15/00190 (to JP-O), and FEDER ‘Una manera de hacer Europa’; and by LaMarató 2016 (303/C/2016) (to JJ). JJ is recipient of a Miguel Servet Type 1 contract (CP13/00070; ISCIII). KAM-L is recipient of a AGAUR grant FI-DGR2014 (Generalitat de Catalunya). CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is a project of the Instituto de Salud Carlos III. Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau is accredited by the Generalitat de Catalunya as Centre de Recerca de Catalunya (CERCA).Peer reviewe

Nicotinamide Prevents Apolipoprotein B-Containing Lipoprotein Oxidation, Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice

Altres ajuts: Fundació La Marató de TV3 2016 (303/C/2016) (201602.31) (to J.J.) and (97/C/2016) (201605-31) (to A.F.V.).The potential of nicotinamide (NAM) to prevent atherosclerosis has not yet been examined. This study investigated the effect of NAM supplementation on the development of atherosclerosis in a mouse model of the disease. The development of aortic atherosclerosis was significantly reduced (NAM low dose: 45%; NAM high dose: 55%) in NAM-treated, apolipoprotein (Apo)E-deficient mice challenged with a Western diet for 4 weeks. NAM administration significantly increased (1.8-fold) the plasma concentration of proatherogenic ApoB-containing lipoproteins in NAM high-dose (HD)-treated mice compared with untreated mice. However, isolated ApoB-containing lipoproteins from NAM HD mice were less prone to oxidation than those of untreated mice. This result was consistent with the decreased (1.5-fold) concentration of oxidized low-density lipoproteins in this group. Immunohistochemical staining of aortas from NAM-treated mice showed significantly increased levels of IL-10 (NAM low-dose (LD): 1.3-fold; NAM HD: 1.2-fold), concomitant with a significant decrease in the relative expression of TNFα (NAM LD: −44%; NAM HD: −57%). An improved anti-inflammatory pattern was reproduced in macrophages cultured in the presence of NAM. Thus, dietary NAM supplementation in ApoE-deficient mice prevented the development of atherosclerosis and improved protection against ApoB-containing lipoprotein oxidation and aortic inflammation

Administration of CORM-2 inhibits diabetic neuropathy but does not reduce dyslipidemia in diabetic mice.

The antinociceptive effects of the carbon monoxide-releasing molecule tricarbonyldichlororuthenium (II) dimer (CORM-2) during chronic pain are well documented, but most of its possible side-effects remain poorly understood. In this work, we examine the impact of CORM-2 treatment on the lipoprotein profile and two main atheroprotective functions attributed to high-density lipoprotein (HDL) in a mouse model of type 1 diabetes while analyzing the effect of this drug on diabetic neuropathy. Streptozotocin (Stz)-induced diabetic mice treated with CORM-2 (Stz-CORM-2) or vehicle (Stz-vehicle) were used to evaluate the effect of this drug on the modulation of painful diabetic neuropathy using nociceptive behavioral tests. Plasma and tissue samples were used for chemical and functional analyses, as appropriate. Two main antiatherogenic properties of HDL, i.e., the ability of HDL to protect low-density lipoprotein (LDL) from oxidation and to promote reverse cholesterol transport from macrophages to the liver and feces in vivo (m-RCT), were also assessed. Stz-induced diabetic mice displayed hyperglycemia, dyslipidemia and pain hypersensitivity. The administration of 10 mg/kg CORM-2 during five consecutive days inhibited allodynia and hyperalgesia and significantly ameliorated spinal cord markers (Cybb and Bdkrb1expression) of neuropathic pain in Stz mice, but it did not reduce the combined dyslipidemia shown in Stz-treated mice. Its administration to Stz-treated mice led to a significant increase in the plasma levels of cholesterol (∼ 1.4-fold vs. Ctrl, ∼ 1.3- fold vs. Stz-vehicle; p < 0.05) and was attributed to significant elevations in both non-HDL (∼ 1.8-fold vs. Ctrl; ∼ 1.6-fold vs. Stz-vehicle; p < 0.05) and HDL cholesterol (∼ 1.3-fold vs. Ctrl, ∼ 1.2-fold vs. Stz-vehicle; p < 0.05). The increased HDL in plasma was not accompanied by a commensurate elevation in m-RCT in Stz-CORM-2 compared to Stz-vehicle mice; instead, it was worsened as revealed by decreased [3H]-tracer trafficking into the feces in vivo. Furthermore, the HDL-mediated protection against LDL oxidation ex vivo shown by the HDL isolated from Stz-CORM-2 mice did not differ from that obtained in Stz-vehicle mice. In conclusion, the antinociceptive effects produced by a high dose of CORM-2 were accompanied by antioxidative effects but were without favorable effects on the dyslipidemia manifested in diabetic mice