NRF2 is essential for adaptative browning of white adipocytes.

White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for ß3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.

The prevalence and major determinants of non-compliance with anti-seizure medication among children.

Background: A wide range of adherence to the use of anti-seizure medications has been reported among children with the disease, and accordingly, various factors on the degree of adherence to the drug have been reported. But in our society, there is no clear picture of drug adherence and related factors among children with seizures. We evaluated the frequency of adherence to anti-seizure medication as well as related factors. Methods: This cross-sectional study was conducted on 120 children with epilepsy who referred to Ali Asghar Hospital in Tehran, Iran, during 2019 and 2020. Along with demographic characteristics, adherence to antiepileptic medications was assessed by the Modified Morisky Scale (MMS). Results: The overall frequency of adherence to anti-seizure medications among children was reported to be about 41.7%. Among all baseline characteristics, much higher adherence was revealed in patients with educated parents. The rate of drug adherence in children with a history of perinatal morbidities was much lower than in other patients. The type of seizure could also affect the rate of drug adherence as the highest and the lowest adherence was found concerning focal impaired awareness seizure (57.1%) and atonic seizures (11.1%) indicating a significant difference (P = 0.022). The most common causes of non-adherence to treatment were expressing inability to treat the patient (23.0%), parents' forgetfulness to give medicine to the child (18.3%), and not taking medication when traveling or leaving home (16.7%). Conclusion: The lower level of education of the parents, type of seizure, as well as the presence ofunderlying perinatal morbidity in the child can predict non-compliance with anticonvulsant medication regimens among affected children.