Fructose, glucocorticoids and adipose tissue: Implications for the metabolic syndrome

The modern Western society lifestyle is characterized by a hyperenergetic, high sugar containing food intake. Sugar intake increased dramatically during the last few decades, due to the excessive consumption of high-sugar drinks and high-fructose corn syrup. Current evidence suggests that high fructose intake when combined with overeating and adiposity promotes adverse metabolic health effects including dyslipidemia, insulin resistance, type II diabetes, and inflammation. Similarly, elevated glucocorticoid levels, especially the enhanced generation of active glucocorticoids in the adipose tissue due to increased 11β-hydroxysteroid dehydrogenase 1 (11β -HSD1) activity, have been associated with metabolic diseases. Moreover, recent evidence suggests that fructose stimulates the 11β -HSD1-mediated glucocorticoid activation by enhancing the availability of its cofactor NADPH. In adipocytes, fructose was found to stimulate 11β -HSD1 expression and activity, thereby promoting the adipogenic effects of glucocorticoids. This article aims to highlight the interconnections between overwhelmed fructose metabolism, intracellular glucocorticoid activation in adipose tissue, and their metabolic effects on the progression of the metabolic syndrome. © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license

Proton pump inhibitors and serum magnesium levels in patients with Torsades de Pointes

Background: Torsades de pointes (TdP) is a life-threatening ventricular tachycardia occurring in long QT-syndrome patients. It usually develops when multiple QT-prolonging factors are concomitantly present, more frequently drugs and electrolyte imbalances. Since proton-pump inhibitors (PPIs)-associated hypomagnesemia is an increasingly recognized adverse event, PPIs were recently included in the list of drugs with conditional risk of TdP, despite only few cases of TdP in PPI users have been reported so far. Objectives: Aim of the present study is to evaluate whether PPI-induced hypomagnesemia actually has a significant clinical impact on the risk of TdP in the general population. Methods: Forty-eight unselected patients who experienced TdP were consecutively enrolled (2008-2017). Shortly after the first TdP episode, in those patients who did not receive magnesium sulfate and/or potassium or calcium replacement therapy, serum electrolytes were measured and their relationship with PPI usage analyzed. Results: Many patients (28/48, 58%) were under current PPI treatment when TdP occurred. Among TdP patients in whom serum electrolyte determinations were obtained before replacement therapy (27/48), those taking PPIs had significantly lower serum magnesium levels than those who did not. Hypomagnesemia occurred in ~40% of patients receiving PPIs (6/14), in all cases after an extended treatment (> 2 weeks). In patients taking PPIs the mean QT-prolonging risk factor number was significantly higher than in those who did not, a difference which was mainly driven by lower magnesium levels. Conclusions: In unselected TdP patients, PPI-induced hypomagnesemia was common and significantly contributed to their cumulative arrhythmic risk. By providing clinical support to current recommendations, our data confirm that more awareness is needed when a PPI is prescribed, specifically as regards the risk of life-threatening arrhythmias

Searching novel therapeutic targets for scleroderma: P2X7-receptor is UP-regulated and promotes a fibrogenic phenotype in systemic sclerosis fibroblasts

Objectives: Systemic sclerosis (SSc) is a connective tissue disorder presenting fibrosis of the skin and internal organs, for which no effective treatments are currently available. Increasing evidence indicates that the P2X7 receptor (P2X7R), a nucleotide-gated ionotropic channel primarily involved in the inflammatory response, may also have a key role in the development of tissue fibrosis in different body districts. This study was aimed at investigating P2X7R expression and function in promoting a fibrogenic phenotype in dermal fibroblasts from SSc patients, also analyzing putative underlying mechanistic pathways. Methods: Fibroblasts were isolated by skin biopsy from 9 SSc patients and 8 healthy controls. P2X7R expression, and function (cytosolic free Ca2+ fluxes, α-smooth muscle actin [α-SMA] expression, cell migration, and collagen release) were studied. Moreover, the role of cytokine (interleukin-1β, interleukin-6) and connective tissue growth factor (CTGF) production, and extracellular signal-regulated kinases (ERK) activation in mediating P2X7R-dependent pro-fibrotic effects in SSc fibroblasts was evaluated. Results: P2X7R expression and Ca2+ permeability induced by the selective P2X7R agonist 2'-3'-O-(4-benzoylbenzoyl)ATP (BzATP) weremarkedly higher in SSc than control fibroblasts. Moreover, increased aSMA expression, cell migration, CTGF, and collagen release were observed in lipopolysaccharides-primed SSc fibroblasts after BzATP stimulation. While P2X7-induced cytokine changes did not affect collagen production, it was completely abrogated by inhibition of the ERK pathway. Conclusion: In SSc fibroblasts, P2X7R is overexpressed and its stimulation induces Ca2+-signaling activation and a fibrogenic phenotype characterized by increased migration and collagen production. These data point to the P2X7R as a potential, novel therapeutic target for controlling exaggerated collagen deposition and tissue fibrosis in patients with SSc

Arterial Tortuosity Syndrome: a vitamin C compartmentation disease?

Arterial tortuosity syndrome (ATS, MIM #208050) is a rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries and a propensity towards aneurysm formation and vascular dissection. ATS is caused by mutations in SLC2A10 encoding the facilitative glucose transporter 10 (GLUT10), whose role in the ATS pathogenesis remains still controversial. We recently showed that GLUT10 deficiency causes the dysregulation of several genes/proteins involved in TGFβ signaling, extracellular matrix architecture and pathways that control oxidative stress response. GLUT10 should be located intracellularly; however, neither the exact localization, i.e., nuclear membrane, mitochondria, or endoplasmic reticulum (ER), nor the transported substances, i.e., glucose or dehydroascorbic acid (DAA), have been demonstrated. Here, we demonstrate that GLUT10 facilitates DAA uptake into the endomembranes and, in particular, into ER. GLUT10 produced by in vitro translation and incorporated into proteoliposomes efficiently transports DAA. Silencing of GLUT10 in hTERT immortalized human fibroblasts compromised DAA transport activity through the endomembranes. Similarly, in plasma membrane-permeabilized ATS fibroblasts a huge decrease in DAA transport was observed and the stable re-expression of GLUT10 restored the impaired DAA transport activity. Immunocytochemistry of human control fibroblasts showed a perinuclear abundance of GLUT10. Immunoblotting of subcellular fractions from human control fibroblasts revealed that GLUT10 was principally present in the microsomal fraction, containing ER-derived vesicles, as showed by the presence of the specific ER marker proteins GRP78 and GRP94, and by the almost complete absence of mitochondrial and cytoplasmic markers, VDAC1, cyclophilin D, and GAPDH, respectively. Transient expression of V5-tagged GLUT10 in ATS patients’ fibroblasts and co-localization experiments with the specific ER marker PDI definitely confirmed the ER localization of GLUT10. Overall, the present findings demonstrate that GLUT10 facilitates DAA uptake into the ER lumen and likely to the nucleoplasm through the nuclear envelope, which is a subdomain of the ER. Our findings support both “antioxidant-” and “enzyme cofactor-” models of a vitamin C-related pathology. Indeed, AA acts as an antioxidant/electron acceptor protecting against oxidative stress-induced cellular damage by scavenging free radicals also during the process of oxidative protein folding. Furthermore, AA is an essential cofactor for α-ketoglutarate-dependent dioxygenases, such as prolyl and lysyl hydroxylases inside the ER and for ten-eleven translocation demethylases and the Jumonji protein family present in the nucleus. Thus, shortage of AA in the lumenal compartments of the secretory pathway and in the nucleoplasm can depress the production of extracellular matrix proteins at both post-translational and epigenetic levels

Teratogenic Effects of Diatom Metabolites on Sea Urchin Paracentrotus lividus Embryos

The diatom-derived polyunsaturated aldehydes (PUAs), 2-trans,4-trans-decadienal, 2-trans,4-trans-octadienal, 2-trans,4-trans,7-octatrienal, 2-trans,4-trans-heptadienal, as well as tridecanal were tested on early and later larval development in the sea urchin Paracentrotus lividus. We also tested the effect of some of the more abundant diatom polyunsaturated fatty acids (PUFAs) on development, in particular 5,8,11,14,17-eicosapentaenoic acid (EPA), one of the main precursors of diatom PUAs, as well as 4,7,10,13,16,19-docosahexaenoic acid (DHA), 6,9,12,15-octadecatetraenoic acid (stearidonic acid), 6,9,12-octadecatrienoic acid (γ-linolenic acid) and 9,12-octadecadienoic acid (linoleic acid). PUAs blocked sea urchin cell cleavage in a dose dependent manner and with increasing chain length from C7 to C10 PUAs, with arrest occurring at 27.27 μM with heptadienal, 16.13 μM with octadienal, 11.47 μM with octatrienal and 5.26 μM with decadienal. Of the PUFAs tested, only EPA and stearidonic acid blocked cleavage, but at much higher concentrations compared to PUAs (331 μM for EPA and 181 μM for stearidonic acid). Sub-lethal concentrations of decadienal (1.32–5.26 μM) delayed development of embryos and larvae which showed various degrees of malformations depending on the concentrations tested. Sub-lethal concentrations also increased the proportion of TUNEL-positive cells indicating imminent death in embryos and larvae. Using decadienal as a model PUA, we show that this aldehyde can be detected spectrophotometrically for up to 14 days in f/2 medium