No abstract

Intermittent fasting blunts inflammation in asthma 1 and rheumatoid arthritis 2 , suggesting that fasting may be exploited as an immune-modulatory intervention. However, mechanisms underpinning anti-inflammatory effects of fasting remain poorly characterized 3 , 4 , 5 . Here, we show that fasting in humans is sufficient to blunt CD4 + T helper cell responsiveness. RNA-seq and flow cytometric immunophenotyping of peripheral blood mononuclear cells (PBMCs) from volunteers subjected to overnight or 24-hour fasting, and 3-hours of refeeding implicate that fasting blunts CD4 + T helper cell activation and differentiation. Transcriptomic analysis reveal that the longer fast-duration has a more robust effect on CD4 + T cell biology. Through bioinformatic analyses, we identify the transcription factor FOXO4 and its canonical target FKBP5 as a potential fasting-responsive regulatory axis. Genetic gain- or loss-of-function of FOXO4 and FKBP5 is sufficient to modulate Th1 and Th17 cytokine production. Moreover, we find that fasting-induced or genetic overexpression of FOXO4 and FKBP5 is sufficient to downregulate mTORC1 signaling and suppress STAT1/3 activation. Our results identify FOXO4-FKBP5 as a novel fasting-induced, STAT-mediated, regulatory pathway to blunt human CD4 + T helper cell responsiveness.

Exposure to inorganic arsenic in the general population occurs mainly from drinking water and food sources. This study examined the association between rice consumption and urinary concentrations of arsenic in US adults, aged 20-85 years, in the 2003-2006 National Health and Nutrition Examination Survey. Significantly higher geometric means of creatinine-corrected urinary concentrations of total arsenic (TAs) and dimethylarsinic acid (DMA) were found in participants who consumed rice more than twice per week, compared to the reference group. Multivariate logistic regression analysis revealed a statistically significant association between rice consumption and urinary concentrations of TAs [odds ratio (OR) = 1.51 (1.08, 2.09)] and DMA [OR = 2.24 (1.57, 3.21)] after adjustment for demographic variables, seafood intake (the main source of organic arsenic), and source of drinking water. Furthermore, significant variations in rice consumption and urinary concentrations of arsenic were observed in different racial groups. This study demonstrated that rice consumption contributed to inorganic arsenic exposure in US adults.

The regulatory control of cardiac endoplasmic reticulum (ER) stress is incompletely characterized. As ER stress signaling upregulates the E3-ubiquitin ligase Parkin, we investigated the role of Parkin in cardiac ER stress. Parkin knockout mice exposed to aortic constriction-induced cardiac pressure-overload or in response to systemic tunicamycin (TM) developed adverse ventricular remodeling with excessive levels of the ER regulatory C/EBP homologous protein CHOP. CHOP was identified as a Parkin substrate and its turnover was Parkin-dose and proteasome-dependent. Parkin depletion in cardiac HL-1 cells increased CHOP levels and enhanced susceptibility to TM-induced cell death. Parkin reconstitution rescued this phenotype and the contribution of excess CHOP to this ER stress injury was confirmed by reduction in TM-induced cell death when CHOP was depleted in Parkin knockdown cardiomyocytes. Isogenic Parkin mutant iPSC-derived cardiomyocytes showed exaggerated ER stress induced CHOP and apoptotic signatures and myocardium from subjects with dilated cardiomyopathy showed excessive Parkin and CHOP induction. This study identifies that Parkin functions to blunt excessive CHOP to prevent maladaptive ER stress-induced cell death and adverse cardiac ventricular remodeling. Additionally, Parkin is identified as a novel post-translational regulatory moderator of CHOP stability and uncovers an additional stress-modifying function of this E3-ubiquitin ligase.