FOXO 1a and FOXO 3a gene polymorphisms in association with metabolic syndrome

The prevalence and magnitude of childhood and adult obesity and diabetes are increasing dramatically. FOXO 1a and FOXO 3a will be evaluated in this study, in an effort to identify genetic polymorphisms in potential candidate genes that may be associated with body mass index (BMI), and metabolic syndrome (MS). Also to assess whether there is a relation between insulin sensitivity, and genotype, we will test the relation between fasting insulin, glucose, insulin resistance, insulin secretion and genotype.A total number of 248 presenting normal, overweight and obese individuals were recruited; 100 children and 148 adults of both sexes. They were divided by body mass index as follows, normal, overweight and obese. Lipid profile, fasting glucose and insulin HOMA-IR and HOMA-β index and RT-PCR for FOXO 1a and FOXO 3a were performed.An association was found among the studied group (children and adults) as regards foxo3a gene polymorphism and HOMA IR, HOMA B index and T-cholesterol (P = 0.022, 0.011 and 0.028, respectively), while there was only an association between LDL-C and foxo1a gene polymorphism among the studied group of children and adults (P = 0.023).In this study we demonstrated that FOXO3a mutant is correlated with HOMA-IR (marker of insulin resistance), HOMA-B index (marker of insulin secretion) and total cholesterol while as regards FOXO1a there was only an association between LDL cholesterol and mutant type of FOXO1a.     

FOXO转录因子调控哺乳动物的细胞周期和凋亡

细胞周期和细胞凋亡是哺乳动物细胞生命活动的两大关键事件。FOXO在哺乳动物的细胞分化、增殖、生长、衰老等生命活动中发挥着重要的调控作用,并且参与细胞周期和凋亡的调控,是细胞生死的开关,因此FOXO已成为肿瘤、癌症科学研究的热点之一。在机体细胞中,FOXO受到上游信号分子PI3K/PKB、Ras等的激活或抑制从而调节下游信号分子FasL、Bim、p27kip1、cyclinG2、cyclinB、p130、GADD45等,并与其他细胞周期调控因子形成复杂的信号网络,调节哺乳动物细胞周期的进程和凋亡事件。     

多功能的转录因子FOXO3a

转录因子FOXO3a是Forkhead家族的一个重要成员,作为人体内七大神秘基因之一,广泛参与细胞的信号转导、生长发育、凋亡及抗氧化应激,并具有延长寿命的作用。FOXO3a是广为人知的抑癌基因,其作用包括促进细胞凋亡、抑制血管生成等。然而,近年米发现慢性粒细胞性白血病干细胞依赖于FOXO3a,这一颠覆性的研究结果促使人们重新认识FOXO3a——这个神秘的转录网子。     

The PKB/FOXO switch in aging and cancer

Aging is characterized by the general decline in tissue and body function and the increased susceptibility to age-related pathologies, such as cancer. To maintain optimal tissue and body function, organisms have developed complex mechanisms for tissue homeostasis. Importantly, it is becoming apparent that these same mechanisms when deregulated also result in the development of age-related disease. The build in failsafe mechanisms of homeostasis, which prevent skewing toward disease, themselves contribute to aspects of aging. Thus, longevity is limited by an intrinsic trade-off between optimal tissue function and disease. Consequently, aging and age-related diseases, such as cancer and diabetes are driven by the same genetic determinants. Illustrative in this respect is the insulin/IGF-1 signaling pathway acting through PI3K/PKB and FOXO. Loss of PKB signaling contributes to diabetes, whereas gain of function of PKB drives cancer. Enhanced FOXO activity, at least in model organism contributes to extended lifespan and acts as a tumor suppressive mechanism. Here, we focus on the linkage between PKB and FOXO as a central switch in contributing to tissue homeostasis and age-related diseases in particular cancer. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging.     

FOXO1 delays skeletal muscle regeneration and suppresses myoblast proliferation

Unloading stress, such as bed rest, inhibits the regenerative potential of skeletal muscles; however, the underlying mechanisms remain largely unknown. FOXO1 expression, which induces the upregulated expression of the cell cycle inhibitors p57 and Gadd45α, is known to be increased in the skeletal muscle under unloading conditions. However, there is no report addressing FOXO1-induced inhibition of myoblast proliferation. Therefore, we induced muscle injury by cardiotoxin in transgenic mice overexpressing FOXO1 in the skeletal muscle (FOXO1-Tg mice) and observed regeneration delay in skeletal muscle mass and cross-sectional area in FOXO1-Tg mice. Increased p57 and Gadd45α mRNA levels, and decreased proliferation capacity were observed in C2C12 myoblasts expressing a tamoxifen-inducible active form of FOXO1. These results suggest that decreased proliferation capacity of myoblasts by FOXO1 disrupts skeletal muscle regeneration under FOXO1-increased conditions, such as unloading.     

pH值对FOXO1、GDF-8基因反义RNA寡核苷酸吸收的影响

研究不同pH值下,口服靶向FOXO1与GDF-8基因反义RNA寡核苷酸药物对药效的影响.化学合成靶向FOXO1与GDF-8基因的有效反义RNA寡核苷酸片段,调节药物PH值,通过灌胃方式给药,给药20 d后处死小鼠,进行体重,腿部肌肉增长情况分析.提取腿部肌肉组织总RNA,用real time PCR检测FOXO1与GDF-8基因的表达.结果表明,服用RNA oligos的试验组小鼠腿部肌肉重量均比对照组肌肉重量增长快.其中pH为7.0的RNA oligos的效果比pH为5.0的效果好, pH9.0的RNA oligos的作用效果最弱.与小鼠体重变化结果一致,real time PCR检测实验组FOXO1与GDF-8基因转录水平较对照组均有明显下降,其中服用pH为7.0的RNA oligos的下降最多.因此,口服靶向FOXO1与GDF-8基因的反义RNA寡核苷酸药物的最适pH值应为中性偏酸.