The Value of SIRT1/FOXO1 Signaling Pathway in Early Detection of Cardiovascular Risk in Children with ß-Thalassemia Major.

Background: Atherosclerosis represents one of the major causes of morbidity in children with ß-thalassemia major (ß-TM). Aim: This study was designed to investigate SIRT1-FOXO1 signaling in ß-TM children and their role in early detection of premature atherosclerosis. Methods: We equally subdivided 100 Egyptian children aged 6−14 years with ß-TM according to carotid intima media thickness (CIMT) into 50 with CIMT < 0.5 mm and 50 with CIMT ≥ 0.5 mm, and 50 healthy children of matched age were included. They were subjected to evaluation of SIRT1, heat shock protein 72 (HSP72), and hepcidin levels via ELISA and forkhead box protein 1 (FOXO1) mRNA expression using real-time PCR in PBMCs; meanwhile, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase activities were evaluated spectrophotometrically. Results: Our results show significantly high values for CIMT, ß-stiffness, atherogenic index of plasma (AIP), MDA, HSP72 and FOXO1, ferritin with significantly low hepcidin, SOD, catalase, and SIRT1 in ß-TM as compared to controls with a more significant difference in ß-TM with CIMT ≥ 0.5 mm than those with CIMT < 0.5 mm. A significant positive correlation between CIMT and MDA, HSP72, and FOXO1 gene expression was found, while a significant negative correlation with hepcidin, SOD, catalase, and SIRT1 was found. FOXO1 gene expression and HSP72 levels were the strongest independent determinants of CIMT. Conclusion: In ß-TM, FOXO1 signaling is activated with low levels of SIRT1, and this is attributed to accelerated atherosclerosis in ß-TM, which would be crucial in prediction of atherosclerosis.

Soluble receptor and gene polymorphism for AGE: relationship with obesity and cardiovascular risks.

BACKGROUND: Obesity in adolescents has quadrupled in the past 30 y. Markers for cardiovascular risks are needed in this population. We hypothesized that soluble receptor for advanced glycation end products (sRAGE) and asymmetric dimethyl arginine (ADMA) can correlate with carotid intima-media thickness (cIMT), a known index of subclinical atherosclerosis. We also aimed to evaluate the frequency of (Gly82Ser) RAGE gene polymorphism in obese adolescents. METHODS: Obese and nonobese adolescents were evaluated in a cross-sectional study for lipid profile, insulin resistance, ADMA, sRAGE, and RAGE gene (Gly 82 Ser) polymorphism. We measured cIMT in all subjects and performed correlation analyses with all markers. RESULTS: The study included 50 obese and 40 healthy control adolescents. Compared to controls, obese subjects had less sRAGE (P = 0.02) and greater cIMT (P = 0.006), insulin resistance (P < 0.0001), and ADMA (P < 0.0001). In a multivariate linear regression model, sRAGE was associated with cIMT (ß = 0.28, P = 0.04). Both GS and SS genotypes of RAGE were more frequent in obese than controls (P = 0.04). CONCLUSION: Increased ADMA and decreased sRAGE are associated with cardiovascular risks in obese adolescents. The S allele in RAGE gene is more frequently detected with obesity. The role of RAGE gene and mechanisms leading to cardiovascular risks need further studying.

Favorable effects of vildagliptin on metabolic and cognitive dysfunctions in streptozotocin-induced diabetic rats.

Progression of diabetes mellitus is accompanied by metabolic disorders together with psychological deficits including cognitive dysfunctions. Herein, we used a murine streptozotocin (STZ)-induced diabetes to investigate the beneficial effects of vildagliptin not only on metabolic abnormalities, but also on diabetes-induced cognitive decline. Sixty rats were divided randomly and equally into 2 groups; one remains normal and the other serves as STZ- induced diabetic. Both groups were further divided equally into 2 groups; one received vehicle and the other received oral vildagliptin for 8 weeks. Cognitive behavior was assessed using novel object recognition test. Blood samples were collected to measure metabolic parameters and dipeptidyl peptidase (DPP)-IV activity. Brains were removed and investigated for the levels of inflammatory and oxidative stress markers malondialdehyde (MDA), superoxide dismutase (SOD) and tumor necrosis factor-α (TNF-α), in addition to brain-derived neurotrophic factor (BDNF) and relative expression of nuclear factor kappa B (NF-κB)/p65. Treatment of STZ-induced diabetic rats with vildagliptin increased their body weight and corrected diabetes-induced memory and learning impairment. Moreover, vildagliptin significantly decreased serum levels of glucose and lipids (except high density lipoprotein) together with brain MDA, TNF-α, serum DPP-IV activities and NF-κB/p65 gene expression. On the other hand, vildagliptin significantly increased brain BDNF, SOD as well as serum insulin. Results suggested that vildagliptin has a protective role in counteracting both metabolic abnormalities and memory deficits in diabetic rats, possibly via its anti-hyperglycemic, anti-inflammatory, antioxidant effects, together with reduction of brain NF-κB/p65 over expression.

A proliferation-inducing ligand in atopic dermatitis and vitiligo.

BACKGROUND: A proliferation-inducing ligand (APRIL) is a tumor necrosis factor (TNF) superfamily member ligand that stimulates B cells in vitro and in vivo. It also plays an important role in T cell activation and survival. OBJECTIVES: This study was conducted to evaluate serum levels of APRIL in patients with atopic dermatitis (AD) and vitiligo and their correlation with disease activity. METHODS: A total of 100 subjects were included; these comprised 40 AD patients, 40 vitiligo patients, and 20 control subjects. Serum APRIL levels were measured and their relationships with the severity of AD and activity of vitiligo evaluated according to scores on the SCORAD (SCORing of Atopic Dermatitis) and VIDA (Vitiligo Disease Activity) indices, respectively. RESULTS: The serum level of APRIL was significantly higher in AD patients than in the control group. Serum APRIL in patients with severe AD showed a statistically significant difference with serum APRIL in patients with either mild or moderate AD. Serum APRIL was significantly higher in vitiligo patients than in the control group. Differences in serum APRIL among patients with different VIDA scores were significant only between patients with VIDA scores of +1 and +4. Statistically significant positive correlations emerged between serum APRIL and activity of AD (r = 0.939) and vitiligo (r = 0.740). CONCLUSIONS: APRIL may play a role in the pathogeneses of AD and vitiligo and could be used as an objective marker for the assessment of AD severity and vitiligo activity. Further studies are required to clarify the precise mechanism of APRIL in the pathogeneses of AD and vitiligo and to test the possible use of APRIL inhibitors as novel modalities of therapy.

Taurine is more effective than melatonin on cytochrome P450 2E1 and some oxidative stress markers in streptozotocin-induced diabetic rats.

Melatonin and taurine have alleviative effects in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were divided into nondiabetic, diabetic, diabetic melatonin supplemented and diabetic taurine supplemented groups. At the end of the study, both blood and liver were collected for determination of some oxidative stress parameters, and hepatic cytochrome P450 2E1 (CYP2E1) enzyme activity and gene expression. An increased CYP2E1 activity and expression level with a concomitant significant change in oxidative stress parameters were found in STZ-induced diabetic rats. Taurine or melatonin supplementation to the diabetic rats alleviated these experimental parameters with a more significant effect for taurine than that of melatonin. Suppression of ß-hydroxybutyrate (ß-HB) production by taurine can be one of the mechanisms of a reduction in CYP2E1. Taurine was effective more than melatonin in reducing CYP2E1 activity and expression; therefore antioxidants might prove beneficial in type 1 diabetes associated with manifestations of liver injury.

Effect of histidine on autotaxin activity in experimentally induced liver fibrosis.

The aim of this study was to explain whether serum autotaxin (ATX) activity might be a target for regulation of liver fibrosis and to evaluate the hepatoprotective and antifibrotic effects of histidine in thioacetamide (TAA)-induced liver fibrosis in rats. This study was carried out on 100 Wistar Albino rats, classified into five groups, each containing 20 rats: Group I (control group), Group II: rats were given histidine intraperitoneally, Group III: rats were injected intraperitoneally with TAA, Group IV: rats were injected with L-histidine together with TAA, and Group V: rats were injected with TAA for 1 month then treated with intraperitoneal injection of L-histidine for another month. At the end of experiment, blood and liver were collected for determination of some liver enzymes, plasma total antioxidant capacity (TAC), serum ATX activity, and liver tissue hydroxyproline. Thioacetamide treatment caused significant increases in liver enzymes, ATX activities, and liver hydroxyproline, but a significant decrease in plasma's TAC. Upon treatment with histidine, a significant decrease in liver enzymes, ATX activities, and liver hydroxyproline was observed with a significant increase in plasma TAC in Group IV and a significant decrease in Group V. Histidine as an antioxidant has a protective effect on TAA-induced liver fibrosis; it is beneficial in rats not only by inhibition of collagen synthesis and increasing TAC but also by inhibition of ATX activities thus reducing its capacity to produce lysophosphatidic acid, which has a role in liver fibrosis.

Heamostatic and genetic predisposing factors for stroke in children with sickle cell anemia.

Sickle cell disease (SCD) is a group of genetic disorders characterized by the production of the abnormal hemoglobin S (HbS). Sickle cell anemia (SCA) is the most common type of SCD and represents the homozygous form, in which the individual inherits a double dose of the abnormal gene that codes for hemoglobin S. This study was done to detect cases of silent and clinically overt strokes in children with sickle cell anemia (SCA) and examine predisposing factors for stroke development. The study included 20 children with clinically and hematologically confirmed SCA and 10 controls. They were divided into two groups, group I; included 10 steady state cases and group II; included 10 cases with thrombotic crisis. All subjects were subjected to full clinical examination, measurements of plasma level of: fibrinopeptid A (FPA), thrombin-antithrombin III (TAT), fibrin degradation product (D-dimer) and serum level of platelet endothelial cell adhesion molecule-1 (PECAM-1), and analysis of the ACE gene polymorphism by polymerase chain reaction (PCR). Patients were further subjected to Brain computed axial tomography (CT) scan and/or magnetic resonance imaging (MRI) as well as electro-encephalographic studies (EEG). Silent ischemic brain infarction as evidenced by CT scan and/or MRI was present in one patient in group I (10%) and one patient in group II (10%). On the other hand, two patients in group II (20%) showed clinically overt strokes. Thus, 4 children had silent or clinically overt stroke and the remaining 16 were non-stroke cases. Laboratory results showed that the levels of FPA, TAT, D-dimer and PECAM-1 were significantly elevated in SCA patients both in the steady and crisis states as compared to control, with more evident significant elevation in group II (thrombotic crisis) as compared to group I (steady state). The stroke group showed significant elevation; FPA, TAT, D-dimer and PECAM-1 as compared with non-stroke group. The PCR results showed that the frequencies of both DD genotype and D allele of ACE gene in the thrombotic crisis are significantly higher than in the control group and that all stroke children are of DD genotype. In conclusion, significant increase in FPA, TAT, D-dimer and PECAM-1 levels as well as the presence of ACE D allele of the ACE gene are significant predisposing factors for stroke in children with SCA. Regular follow-up by thorough neurological examination and neuro-imaging studies for early detection of silent brain infarction is recommended.