Propagermanium as a Novel Therapeutic Approach for the Treatment of Endothelial Dysfunction in Type 2 Diabetes.

Propagermanium (PG) has immune modulating activity and anti-inflammatory properties. This work aimed to study the therapeutic efficacy of PG on endothelial and perivascular dysfunction associated with type 2 diabetes. Non-obese type 2 diabetic Goto-Kakizaki (GK) rats were divided into four groups: (1) the control group; (2) the group treated with 50 mg/kg PG; (3) the group fed a high-fat diet (GKHFD); and (4) the group of GKHFD treated with 50 mg/kg PG. PG was given orally for 3 months. Several in vivo parameters and endothelial function were studied in aortas with perivascular adipose tissue PVAT (+) or without PVAT (-). We also determined the vascular inflammation and levels of CD36 in PVAT. In diabetic GK rats, PG did not affect the lipid profile or the results of the intraperitoneal glucose tolerance test. Instead, it improved the fasting glucose levels (18%, p < 0.01), insulin resistance (32%, p < 0.05), endothelial function (33 and 25% in aortas mounted with (+) or without PVAT (-), p < 0.05), and restored the anticontractile effect of the perivascular adipose tissue by reducing its inflammation (56%, p < 0.05) and oxidative stress profile (55%, p < 0.05). Due to its anti-inflammatory characteristics, PG likely improved endothelial dysfunction and restored the perivascular adipose tissue's anticontractile properties.

WWOX inhibition by Zfra1-31 restores mitochondrial homeostasis and viability of neuronal cells exposed to high glucose.

Diabetes has been associated with an increased risk of cognitive decline and dementia. However, the mechanisms underlying this association remain unclear and no effective therapeutic interventions exist. Accumulating evidence demonstrates that mitochondrial defects are a key feature of diabetes contributing to neurodegenerative events. It has also been demonstrated that the putative tumor suppressor WW domain-containing oxidoreductase 1 (WWOX) can interact with mitochondria in several pathological conditions. However, its role in diabetes-associated neurodegeneration remains unknown. So, this study aimed to evaluate the role of WWOX activation in high glucose-induced neuronal damage and death. Our experiments were mainly performed in differentiated SH-SY5Y neuroblastoma cells exposed to high glucose and treated (or not) with Zfra1-31, the specific inhibitor of WWOX. Several parameters were analyzed namely cell viability, WWOX activation (tyrosine 33 residue phosphorylation), mitochondrial function, reactive oxygen species (ROS) production, biogenesis, and dynamics, autophagy and oxidative stress/damage. The levels of the neurotoxic proteins amyloid ß (Aß) and phosphorylated Tau (pTau) and of synaptic integrity markers were also evaluated. We observed that high glucose increased the levels of activated WWOX. Interestingly, brain cortical and hippocampal homogenates from young (6-month old) diabetic GK rats showed increased levels of activated WWOX compared to older GK rats (12-month old) suggesting that WWOX plays an early role in the diabetic brain. In neuronal cells, high glucose impaired mitochondrial respiration, dynamics and biogenesis, increased mitochondrial ROS production and decreased mitochondrial membrane potential and ATP production. More, high glucose augmented oxidative stress/damage and the levels of Aß and pTau proteins and affected autophagy, contributing to the loss of synaptic integrity and cell death. Of note, the activation of WWOX preceded mitochondrial dysfunction and cell death. Importantly, the inhibition of WWOX with Zfra1-31 reversed, totally or partially, the alterations promoted by high glucose. Altogether our observations demonstrate that under high glucose conditions WWOX activation contributes to mitochondrial anomalies and neuronal damage and death, which suggests that WWOX is a potential therapeutic target for early interventions. Our findings also support the efficacy of Zfra1-31 in treating hyperglycemia/diabetes-associated neurodegeneration.

Circulating Dopamine Is Regulated by Dietary Glucose and Controls Glucagon-like 1 Peptide Action in White Adipose Tissue.

Dopamine directly acts in the liver and white adipose tissue (WAT) to regulate insulin signaling, glucose uptake, and catabolic activity. Given that dopamine is secreted by the gut and regulates insulin secretion in the pancreas, we aimed to determine its regulation by nutritional cues and its role in regulating glucagon-like peptide 1 (GLP-1) action in WAT. Solutions with different nutrients were administered to Wistar rats and postprandial dopamine levels showed elevations following a mixed meal and glucose intake. In high-fat diet-fed diabetic Goto-Kakizaki rats, sleeve gastrectomy upregulated dopaminergic machinery, showing the role of the gut in dopamine signaling in WAT. Bromocriptine treatment in the same model increased GLP-1R in WAT, showing the role of dopamine in regulating GLP-1R. By contrast, treatment with the GLP-1 receptor agonist Liraglutide had no impact on dopamine receptors. GLP-1 and dopamine crosstalk was shown in rat WAT explants, since dopamine upregulated GLP-1-induced AMPK activity in mesenteric WAT in the presence of the D2R and D3R inhibitor Domperidone. In human WAT, dopamine receptor 1 (D1DR) and GLP-1R expression were correlated. Our results point out a dietary and gut regulation of plasma dopamine, acting in the WAT to regulate GLP-1 action. Together with the known dopamine action in the pancreas, such results may identify new therapeutic opportunities to improve metabolic control in metabolic disorders.

Improvement of Glycaemia and Endothelial Function by a New Low-Dose Curcuminoid in an Animal Model of Type 2 Diabetes.

Curcumin has been suggested as a promising treatment for metabolic diseases, but the high doses required limit its therapeutic use. In this study, a new curcuminoid is synthesised to increase curcumin anti-inflammatory and antioxidant potential and to achieve hypoglycaemic and protective vascular effects in type 2 diabetic rats in a lower dose. In vitro, the anti-inflammatory effect was determined through the Griess reaction, and the antioxidant activity through ABTS and TBARS assays. In vivo, Goto-Kakizaki rats were treated for 2 weeks with the equimolar dose of curcumin (40 mg/kg/day) or curcuminoid (52.4 mg/kg/day). Fasting glycaemia, insulin tolerance, plasma insulin, insulin signalling, serum FFA, endothelial function and several markers of oxidative stress were evaluated. Both compounds presented a significant anti-inflammatory effect. Moreover, the curcuminoid had a marked hypoglycaemic effect, accompanied by higher GLUT4 levels in adipose tissue. Both compounds increased NO-dependent vasorelaxation, but only the curcuminoid exacerbated the response to ascorbic acid, consistent with a higher decrease in vascular oxidative and nitrosative stress. SOD1 and GLO1 levels were increased in EAT and heart, respectively. Altogether, these data suggest that the curcuminoid developed here has more pronounced effects than curcumin in low doses, improving the oxidative stress, endothelial function and glycaemic profile in type 2 diabetes.

Impairment of the angiogenic process may contribute to lower success rate of root canal treatments in diabetes mellitus.

AIM: To investigate the association between root canal treatment outcome, diabetes mellitus, and alterations of the angiogenic process. METHODOLOGY: A retrospective observational study was conducted in healthy (control group, CG) and diabetic (type II diabetes mellitus group, DG) patients after root canal treatment. The follow-up appointments were performed to clinically and radiographically observe symptoms, the healing of periapical lesions and the quality of root fillings. In the animal model study, diabetic Goto-Kakizaki (GK) rats and control Wistar rats were used. After 21 days of pulp exposure and the development of apical periodontitis (AP), the mandibles were removed for scintigraphic, radiographic, histopathological and molecular analyses. Chi-square tests were performed to examine the variables related to endodontic outcome and differences between animal groups were assessed using the Student's t-test. RESULTS: The group of patients with diabetes had a significantly lower rate of success following root canal treatment than the CG (p < .001). Logistic regression suggested that diabetes is a risk factor for success of root canal treatment. In the animal study, GK rats had significantly higher fasting glycaemia at t0 and t21 (p < .001) and triglycerides levels (p < .05) and area under the curve (AUC) during the insulin tolerance test at t21 (p < .001). AP area was significantly greater in GK rats (p < .05). Histologically, diabetic rats had increased signs of periodontal ligament inflammation 21 days after the induction of apical periodontitis, with fibro-hyaline matrix filling and vessel with undefined walls. Wistar rats had significantly increased vascular endothelial growth factor (VEGF) levels and VEGF/Ang-2 ratio 21 days after AP induction (p < .08; p < .07). GK rats had intrinsically lower levels of VEGF than control rats (p < .05), which did not change after AP. CONCLUSION: Diabetes mellitus should be considered as an important factor in the prognosis of root canal treatment and its outcomes over time. Future strategies to improve angiogenesis and tissue repair should be pursued to achieve better root canal treatment outcomes in diabetic patients.

Luteolin Improves Perivascular Adipose Tissue Profile and Vascular Dysfunction in Goto-Kakizaki Rats.

We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. METHODS: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT-) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT. RESULTS: Endothelial function was impaired in diabetic GK rats (47% (GK - PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK - PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products' levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats. CONCLUSIONS: Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.

Adiponectin and sporadic Alzheimer's disease: Clinical and molecular links.

Obesity has been consistently associated with Alzheimer's disease (AD) though the exact mechanisms by which it influences cognition are still elusive and subject of current research. Adiponectin, the most abundant adipokine in circulation, is inversely correlated with adipose tissue dysfunction and seems to be a central player in this association. In fact, different signalling pathways are shared by adiponectin and proteins involved in AD pathophysiology and considerable amount of evidence supports its direct and indirect influence on ß-amyloid and tau aggregates formation. In this paper we present a critical review of cellular, animal and clinical studies which have contributed to a more thorough understanding of the extent to which adiponectin influences the risk of developing AD as well as its progression. Finally, the effect of acetylcholinesterase inhibitors on circulating adiponectin levels, possible therapeutic applications and future research strategies are also discussed.

GLP-1 improves adipose tissue glyoxalase activity and capillarization improving insulin sensitivity in type 2 diabetes.

Methylglyoxal was shown to impair adipose tissue capillarization and insulin sensitivity in obese models. We hypothesized that glyoxalase-1 (GLO-1) activity could be diminished in the adipose tissue of type 2 diabetic obese patients. Moreover, we assessed whether such activity could be increased by GLP-1-based therapies in order to improve adipose tissue capillarization and insulin sensitivity. GLO-1 activity was assessed in visceral adipose tissue of a cohort of obese patients. The role of GLP-1 in modulating GLO-1 was assessed in type 2 diabetic GK rats submitted to sleeve gastrectomy or Liraglutide treatment, in the adipose tissue angiogenesis assay and in the HUVEC cell line. Glyoxalase-1 activity was decreased in visceral adipose tissue of pre-diabetic and diabetic obese patients, together with other markers of adipose tissue dysfunction and correlated with increased HbA1c levels. Decreased adipose tissue GLO-1 levels in GK rats were increased by sleeve gastrectomy and Liraglutide, being associated with overexpression of angiogenic and vasoactive factors, as well as insulin receptor phosphorylation (Tyr1161). Moreover, GLP-1 increased adipose tissue capillarization and HUVEC proliferation in a glyoxalase-dependent manner. Lower adipose tissue GLO-1 activity was observed in dysmetabolic patients, being a target for GLP-1 in improving adipose tissue capillarization and insulin sensitivity.

Myocardial peak systolic velocity-a tool for cardiac screening of HIV-exposed uninfected children.

HIV-uninfected children exposed prenatally to the virus and to prophylactic antiretroviral therapy are at an uncertain risk of long-term myocardial dysfunction. This study aimed to analyse the structure and function of their ventricles and to identify potential screening tools for this at-risk population. One hundred and fifteen children (77 exposed vs 38 controls) aged between 2.7 and 16.2 years were included. An echocardiographic study was performed where both ventricles' dimensions and systolic functions were evaluated. In the left ventricle, parameters related to diastolic function were also analysed. Tissue Doppler values were determined in the basal state and after passive leg raising. Serologic analysis of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was carried out. The two groups had identical ventricular sizes and left ventricular diastolic functions. However, contractility assessed by myocardial peak systolic velocity was significantly inferior in the exposed group. These systolic echocardiographic differences were present despite similar values of NT-proBNP in both groups.Conclusion: HIV-exposed uninfected children may be vulnerable to ventricular systolic dysfunction at long term. Cardiovascular surveillance and periodic monitoring of biventricular function are therefore recommended. Myocardial peak systolic velocity may be a useful screening tool for this purpose.What is Known:• Previous studies on HIV-exposed uninfected children subjected prenatally to antiretroviral therapy have alerted to potential long-term cardiovascular toxicity effects on the left ventricle.What is New:• The study gives new insights on ventricular function and morphology in HIV-exposed uninfected children.• Myocardial peak systolic velocities are significantly inferior in this paediatric sub-group, therefore long-term cardiac surveillance is recommended.

Using Resistin, glucose, age and BMI to predict the presence of breast cancer.

BACKGROUND: The goal of this exploratory study was to develop and assess a prediction model which can potentially be used as a biomarker of breast cancer, based on anthropometric data and parameters which can be gathered in routine blood analysis. METHODS: For each of the 166 participants several clinical features were observed or measured, including age, BMI, Glucose, Insulin, HOMA, Leptin, Adiponectin, Resistin and MCP-1. Machine learning algorithms (logistic regression, random forests, support vector machines) were implemented taking in as predictors different numbers of variables. The resulting models were assessed with a Monte Carlo Cross-Validation approach to determine 95% confidence intervals for the sensitivity, specificity and AUC of the models. RESULTS: Support vector machines models using Glucose, Resistin, Age and BMI as predictors allowed predicting the presence of breast cancer in women with sensitivity ranging between 82 and 88% and specificity ranging between 85 and 90%. The 95% confidence interval for the AUC was [0.87, 0.91]. CONCLUSIONS: These findings provide promising evidence that models combining age, BMI and metabolic parameters may be a powerful tool for a cheap and effective biomarker of breast cancer.

High-fat diet induces a neurometabolic state characterized by changes in glutamate and N-acetylaspartate pools associated with early glucose intolerance: An in vivo multimodal MRI study.

BACKGROUND: Type-2 diabetes mellitus (T2DM) is a metabolic disorder with a broad range of complications in the brain that depend on the conditions that precede its onset, such as obesity and metabolic syndromes. It has been suggested that neurotransmitter and metabolic perturbations may emerge even before the early stages of T2DM and that high-caloric intake could adversely influence the brain in such states. Notwithstanding, evidence for neurochemical and structural alterations in these conditions are still sparse and controversial. PURPOSE: To evaluate the influence of high-fat diet in the neurochemical profile and structural integrity of the rodent brain. STUDY TYPE: Prospective. SUBJECTS: Wistar rats (n = 12/group). FIELD STRENGTH/SEQUENCE: A PRESS, ISIS, RARE, and EPI sequences were performed at 9.4T. ASSESSMENT: Neurochemical and structural parameters were assessed by magnetic resonance spectroscopy, voxel-based morphometry, volumetry, and diffusion tensor imaging. STATISTICAL TESTS: Measurements were compared through Student and Mann-Whitney tests. Pearson correlation was used to assess relationships between parameters. RESULTS: Animals submitted to high-caloric intake gained weight (P = 0.003) and developed glucose intolerance (P < 0.001) but not hyperglycemia. In the hippocampus, the diet induced perturbations in glutamatergic metabolites reflected by increased levels of glutamine (P = 0.016) and glutamatergic pool (Glx) (P = 0.036), which were negatively correlated with glucose intolerance (glutamine, r = -0.804, P = 0.029), suggesting a link with neurometabolic dysregulation. At caudate-putamen, high-fat diet led to a surprising increase in the pool of N-acetylaspartate (P = 0.028). A relation with metabolic changes was again suggested by the negative correlation between glucose intolerance and levels of glutamatergic metabolites in this region (glutamate, r = -0.845, P = 0.014; Glx, r = -0.834, P = 0.020). Neither changes in phosphate compounds nor major structural alterations were observed for both regions. DATA CONCLUSION: We found evidence that high-fat diet-induced obesity leads to distinct early and region-specific metabolic/neurochemical imbalances in the presence of early glucose intolerance even when structural alterations or T2DM are absent. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.

Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation.

Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises.

Glucose and fructose metabolism originates the highly reactive byproduct methylglyoxal (MG), which is a strong precursor of advanced glycation end products (AGE). The MG has been implicated in classical diabetic complications such as retinopathy, nephropathy, and neuropathy, but has also been recently associated with cardiovascular diseases and central nervous system disorders such as cerebrovascular diseases and dementia. Recent studies even suggested its involvement in insulin resistance and beta-cell dysfunction, contributing to the early development of type 2 diabetes and creating a vicious circle between glycation and hyperglycemia. Despite several drugs and natural compounds have been identified in the last years in order to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the endogenous and exogenous sources of MG, also addressing the current controversy about the importance of exogenous MG sources. The mechanisms by which MG changes cell behavior and its involvement in type 2 diabetes development and complications and the pathophysiological implication are also summarized. Particular emphasis will be given to pathophysiological relevance of studies using higher MG doses, which may have produced biased results. Finally, we also overview the current knowledge about detoxification strategies, including modulation of endogenous enzymatic systems and exogenous compounds able to inhibit MG effects on biological systems.

Functional abolition of carotid body activity restores insulin action and glucose homeostasis in rats: key roles for visceral adipose tissue and the liver.

AIMS/HYPOTHESIS: We recently described that carotid body (CB) over-activation is involved in the aetiology of insulin resistance and arterial hypertension in animal models of the metabolic syndrome. Additionally, we have demonstrated that CB activity is increased in animal models of insulin resistance, and that carotid sinus nerve (CSN) resection prevents the development of insulin resistance and arterial hypertension induced by high-energy diets. Here, we tested whether the functional abolition of CB by CSN transection would reverse pre-established insulin resistance, dyslipidaemia, obesity, autonomic dysfunction and hypertension in animal models of the metabolic syndrome. The effect of CSN resection on insulin signalling pathways and tissue-specific glucose uptake was evaluated in skeletal muscle, adipose tissue and liver. METHODS: Experiments were performed in male Wistar rats submitted to two high-energy diets: a high-fat diet, representing a model of insulin resistance, hypertension and obesity, and a high-sucrose diet, representing a lean model of insulin resistance and hypertension. Half of each group was submitted to chronic bilateral resection of the CSN. Age-matched control rats were also used. RESULTS: CSN resection normalised systemic sympathetic nervous system activity and reversed weight gain induced by high-energy diets. It also normalised plasma glucose and insulin levels, insulin sensitivity lipid profile, arterial pressure and endothelial function by improving glucose uptake by the liver and perienteric adipose tissue. CONCLUSIONS/INTERPRETATION: We concluded that functional abolition of CB activity restores insulin sensitivity and glucose homeostasis by positively affecting insulin signalling pathways in visceral adipose tissue and liver.

Teduglutide effects on gene regulation of fibrogenesis on an animal model of intestinal anastomosis.

BACKGROUND: Teduglutide is an enterotrophic analog of glucagon-like peptide 2 approved for the rehabilitation of short-bowel syndrome. This study aims to analyze the effects of teduglutide administration on the gene regulation of fibrogenesis during the intestinal anastomotic healing on an animal model. METHODS: Wistar rats (n = 62) were assigned into four groups: "Ileal Resection and Anastomosis" or "Laparotomy," each one subdivided into "Postoperative Teduglutide Administration" or "No Treatment," and sacrificed at the third or at the seventh days, with ileal sample harvesting. Gene expression of matrix components and remodeling factors (matrix metalloproteinases [Mmp] and tissue inhibitors of metalloproteinases [Timp]) and growth factors was studied by real-time polymerase chain reaction. Net collagen deposition was assessed through the Collagen-to-Mmp-to-Timp ratio of fold change of relative gene expression. RESULTS: Gene expression profiles revealed a balance toward net degradation of collagen at the third day of the intestinal anastomotic healing. Teduglutide appeared to be associated with an overall accumulation of collagen at the third day of the anastomotic repair, attributable to the upregulation of Collagen type 1 alpha 1, Collagen type 3 alpha 1, and Collagen type 4 alpha 1, Timp1, and Timp2 and downregulation of Mmp13 and to a net degradation of collagen at the seventh day, derived from repression of Collagen type 3 alpha 1, Collagen type 5 alpha 1 and Timp1 expression. CONCLUSIONS: Teduglutide appeared to be associated with a favorable influence on fibrogenesis at the third day of the intestinal anastomotic repair and to a trend to fibrolysis at the seventh day.

Dyslipidemia and cardiovascular changes in children.

PURPOSE OF REVIEW: In this review, we firstly highlight the role of dyslipidemia as a trigger in the initiation and progression of endothelial dysfunction, considered the earliest atherosclerotic lesion and patent in children with risk factors.In this context, we also revise methods that reflect the impact of endothelial dysfunction not only on arterial stiffness but also on cardiovascular morphology, namely, the common carotid intima-media thickness and the ventricular geometry. RECENT FINDINGS: In view of its atherogenic burden, the most widely studied lipoprotein has been low density lipoprotein cholesterol. However, the smaller, denser, low density lipoprotein cholesterol particles, the nonhigh density lipoprotein cholesterol fraction, appear to be more atherogenic and a more sensitive cardiovascular risk marker. Studies have shown that in children, atherogenic lipids have also been linked to cardiovascular morphological changes, such as the common carotid intima-media thickness and the ventricular geometry, both independent cardiovascular risk markers. SUMMARY: In infancy, atherosclerosis is a preclinical disorder in which dyslipidemia plays a crucial role. Due to its impact on cardiovascular structures, potentially reversible during childhood, dyslipidemia ought to be managed aggressively to prevent further disease progression that will ultimately culminate in cardiac disease, a leading cause of mortality in adults.

The Force at the Tip--Modelling Tension and Proliferation in Sprouting Angiogenesis.

Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art.

Childhood adiposity: being male is a potential cardiovascular risk factor.

As the earliest atherosclerotic lesions begin during childhood, our aim was to correlate gender-related adiposity to classical cardiovascular risk factors in a group of children.An observational and transversal analysis was carried out in a cohort consisting of 161 children of both sexes, aged 6 to 17 years of age. Waist circumference was correlated to leptin, high-sensitivity C-reactive protein, systolic and diastolic blood pressure, plasma lipids, homeostasis model assessment-insulin resistance, and the left ventricular mass index. After adjusting for age, waist circumference in boys, compared to girls, correlated more strongly and directly to systolic (r = 0.538; p < 0.001) and diastolic blood pressure (ρ = 0.401; p < 0.01), ApoB/ApoA ratio (ρ = 0.515; p < 0.01), high-density lipoprotein cholesterol (r = -0.441; p < 0.001), low-density lipoprotein cholesterol (ρ = 0.280; p < 0.01), triglycerides (ρ = 0.420; p < 0.001), homeostasis model assessment-insulin resistance (ρ = 0.463; p < 0.001), and the left ventricular mass index (ρ = 0.286; p < 0.01). A similar pattern was observed regarding the correlations between leptin, high-sensitivity C-reactive protein, and the above parameters (except between high-sensitivity C-reactive protein and diastolic blood pressure), and also, particularly in boys. CONCLUSION: Although increased childhood adiposity is related to a more adverse metabolic and clinical profile in both genders, males appear to have a potentially greater cardiovascular risk. WHAT IS KNOWN: Obesity is characterized by a chronic low-grade inflammatory process. WHAT IS NEW: Increased adiposity is related to a more pronounced pro-inflammatory response in boys. Childhood male adiposity is a potentially greater cardiovascular risk factor. Arterial hypertension, insulin resistance, and dyslipidemia is more strongly correlated to waist circumference in boys.

Perspectives on mitochondrial uncoupling proteins-mediated neuroprotection.

The integrity of mitochondrial function is essential to cell life. It follows that disturbances of mitochondrial function will lead to disruption of cell function, expressed as disease or even death. Considering that neuronal uncoupling proteins (UCPs) decrease reactive oxygen species (ROS) production at the expense of energy production, it is important to understand the underlying mechanisms by which UCPs control the balance between the production of adenosine triphosphate (ATP) and ROS in the context of normal physiological activity and in pathological conditions. Here we review the current understanding of neuronal UCPs-mediated respiratory uncoupling process by performing a survey in their physiology and regulation. The latest findings regarding neuronal UCPs physiological roles and their involvement and interest as potential targets for therapeutic intervention in brain diseases will also be exploited.

Insulin resistance and beta cell function before and after sleeve gastrectomy in obese patients with impaired fasting glucose or type 2 diabetes.

BACKGROUND: Pathophysiology of type 2 diabetes (T2D) includes insulin resistance (IR) and insufficient insulin secretion. Remission in obese patients can be achieved through surgically induced weight loss. Sleeve gastrectomy is a novel technique for the treatment of morbid obesity, and its effects on the metabolic syndrome and T2D have not yet been fully understood. METHODS: From February 2008 to July 2010, sleeve gastrectomy as stand-alone treatment for severe or morbid obesity was performed in 23 patients with T2D or impaired fasting glucose (IFG). No postoperative complications occurred and patients were dismissed from hospital on day 2 after surgery. Body mass index (BMI), fasting blood glucose (FBG) and fasting insulin were determined before and up to 24 months after surgery. IR and beta cell function were calculated using the modified homeostasis model assessment (HOMA2). RESULTS: BMI, FBG and fasting insulin improved significantly as early as 3 months after surgery. Threefold increased preoperative insulin resistance (3.05) decreased to near-normal values (1.14) during the same period. Interestingly, overall beta cell function diminished at 12 months of follow-up (79.6 %), in comparison with preoperative values (117.8 %). Patients with a markedly reduced preoperative beta cell function (<40 %) did not achieve a complete remission after surgery. CONCLUSIONS: In obese patients with T2D and IFG, commonly characterized by an augmented beta cell function and an increased insulin resistance, sleeve gastrectomy induces remission through reduction of insulin resistance. Preoperative IR and beta cell function calculated by HOMA2 deserve further studies in patients undergoing metabolic surgery.