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.

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.