Electrophilic nitro-fatty acids (NO2-FAs) are endogenously formed by redox reactions of nitric oxide ((.)NO)- and nitrite ((.)NO2)- derived nitrogen dioxide with unsaturated fatty acids. Nitration ...preferentially occurs on polyunsaturated fatty acids with conjugated dienes under physiological or pathophysiological conditions such as during digestion, metabolism and as adaptive inflammatory processes. Nitro-fatty acids are present in free and esterified forms achieving broad biodistribution in humans and experimental models. Structural, functional and biological characterization of NO2-FAs has revealed clinically relevant protection from inflammatory injury in a number of cardiovascular, renal and metabolic experimental models. NO2-FAs are engaged in posttranslational modifications (PTMs) of a selective redox sensitive pool of proteins and regulate key adaptive signaling pathways involved in cellular homeostasis and inflammatory response. Here, we review and update the biosynthesis, metabolism and signaling actions of NO2-FAs, highlighting their diverse protective roles relevant to the cardiovascular system.
Peroxisome proliferator-activated receptors (PPAR) and liver X receptors (LXR) regulate a plethora of biologic processes and key metabolic and physiologic events. Deregulation of their transcription ...and activity is commonly associated with dyslipidemic disorders, diabetes, cancer, and cardiovascular disease. This review addresses recent advances in our understanding of the molecular mechanisms regulating transcription of these nuclear receptors. The heterogeneity of factors regulating their transcription and activity suggests intricate regulatory networks that determine their tissue expression pattern and their responses to pharmacologic agents. Understanding such mechanisms will facilitate unraveling their protective effects in disease as well as the design of effective targeted therapies.
Se evaluó el efecto de la dosis de irradiación UV-C y tiempo de almacenamiento sobre las características fisicoquímicas, microbiológicas y antioxidantes de frutas tropicales mínimamente procesadas. ...Las frutas fueron seleccionadas, clasificadas, lavadas y cortadas, luego se sumergieron en solución combinada de cloruro calcio (1% p/v) y ácido ascórbico (1% p/v) durante 1 min. Posteriormente, se sometieron a dosis de irradiación UV-C (0, 7 y 14 kJ/m2). Finalmente, fueron envasadas en bandejas de poliestireno y recubiertas con película de cloruro de polivinilo microperforada y almacenadas a 5 ºC, con humedad relativa de 85 - 90%, durante 15 días. Cada cinco días, fueron evaluadas pérdida de peso, color, sólidos solubles, firmeza, recuento de bacterias aerobias mesófilas viables y mohos y levaduras, contenido de fenoles totales y flavonoides totales. El efecto de la dosis de irradiación UV-C y el tiempo de almacenamiento sobre las características fisicoquímicas, microbiológicas y antioxidantes fue significativo (p < 0,05). La dosis de irradiación UV-C de 7 kJ/m2 permitió obtener las mejores características fisicoquímicas en mango y mamey, en tanto que la dosis de 14 kJ/m2 en piña. Las mayores características antioxidantes y menor recuento microbiológico se obtuvieron con la dosis de irradiación UV-C de 14 kJ/m2 durante el almacenamiento.
Electrophilic fatty acid nitroalkene derivatives, products of unsaturated fatty acid nitration, exert long-term cardiovascular protection in experimental models of metabolic and cardiovascular ...diseases. The goal of this study is to examine the effects of nitro-fatty acids in the regulation of upstream signalling events in nuclear factor-κB (NF-κB) activation and determine whether low-dose acute administration of nitro-fatty acids reduces vascular inflammation in vivo.
Using NF-κB-luciferase transgenic mice, it was determined that pre-emptive treatment with nitro-oleic acid (OA-NO2), but not oleic acid (OA) inhibits lipopolysaccharide (LPS)-induced NF-κB activation both in vivo and in isolated macrophages. Acute intravenous administration of OA-NO2 was equally effective to inhibit leukocyte recruitment to the vascular endothelium assessed by intravital microscopy and significantly reduces aortic expression of adhesion molecules. An acute treatment with OA-NO2 in vivo yielding nanomolar concentrations in plasma, is sufficient to inhibit LPS-induced Toll-like receptor 4 (TLR4)-induced cell surface expression in leukocytes and NF-κB activation. In vitro experiments reveal that OA-NO2 suppresses LPS-induced TLR4 signalling, inhibitor of κB (IκBα) phosphorylation and ubiquitination, phosphorylation of the IκB kinase (IKK), impairing the recruitment of the TLR4 and TNF receptor associated factor 6 (TRAF6) to the lipid rafts compartments.
These studies demonstrate that acute administration of nitro-fatty acids is effective to reduce vascular inflammation in vivo. These findings reveal a direct role of nitro-fatty acids in the disruption of the TLR4 signalling complex in lipid rafts, upstream events of the NF-κB pathway, leading to resolution of pro-inflammatory activation of NF-κB in the vasculature.
The addition of nitrogen dioxide (NO2) to the double bond of unsaturated fatty acids yields an array of electrophilic nitro-fatty acids (NO2-FA) with unique biochemical and signaling properties. ...During the last decade, NO2-FA have been shown to exert a protective role in various inflammatory and metabolic disorders. NO2-FA exert their biological effects primarily by regulating two central physiological adaptive responses: the canonical inflammatory signaling and metabolic pathways. In this mini-review, we summarize current knowledge on the regulatory role of NO2-FA in the inflammatory and metabolic response via regulation of nuclear factor kappa B (NF-κB) and peroxisome proliferator-activated receptor γ (PPARγ), master regulators of inflammation and metabolism. Moreover, the engagement of novel signaling and metabolic pathways influenced by NO2-FA, beyond NF-κB and PPAR signaling, is discussed herein.
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•NO2-FA modulate key signaling pathways via posttranslational modifications.•NO2-FA inhibit NF-κB via direct p65 nitroalkylation and regulate Toll-like receptor signaling.•NO2-FA are PPARγ ligands that differ from thiazolidinediones in receptor affinity and extent of activation.•This mini-review conveys the protective role of NO2-FA in inflammatory responses and regulation of metabolic pathways.•Content.
Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets ...without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10
) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies ...constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was tested herein in a model of long-term NASH diet-induced liver damage.
Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental model of NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental therapy with OA-NO2. Experimental controls included equimolar amounts of the non-nitrated oleic acid (OA). CLAMS and NMR-based analysis was used for energy metabolism.
CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride (TG) accumulation. Photoacoustic-ultrasound imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1 proteolytic activation and subsequent lipogenesis gene expression by OA-NO2. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, αSMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells.
OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.
En un sentido diferente a lo propuesto por el positivismo metódico, y desde la aceptación matizada de las premisas hermenéuticas, para la Teoría Estructurante del Derecho la interpretación y la ...aplicación carecen de autonomía propiamente dicha. Por tanto, desde la Teoría Estructurante del Derecho, la Norma jurídica es entendida como “producto”, y la resolución de cada caso requiere una nueva producción normativa hasta su entrega como Norma de decisión
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