Neuroactive steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C

Abstract  Fatigue is one of the most common non-specific symptoms associated with several disease states including liver diseases. Recently, it was reported that levels of progesterone metabolites such as allopregnanolone (3α,5α-tetrahydroprogesterone; 3α,5α-THP) and isopregnanolone (3β,5α-THP) were increased in plasma of patients with chronic fatigue syndrome. We hypothesize that THP metabolites might be associated with fatigue commonly observed in chronic liver diseases. We evaluated fatigue scores and plasma levels of five progesterone metabolites in 16 patients with primary biliary cirrhosis (PBC), 12 patients with chronic hepatitis C (CHC) and 11 age-matched controls. The fatigue impact scale (FIS) ratio was significantly increased ( P  < 0.01) in patients with PBC and CHC compared to controls. Plasma levels of 3α,5α-THP and pregnanolone (3α,5β-THP) were significantly increased in PBC and CHC patients. The other progesterone metabolites, i.e. 3β,5α-THP, 3β,5β-THP and 3α,5α-tetrahydrodeoxycorticosterone were either undetectable or detected only in some patients. Plasma levels of 3α,5α-THP and 3α,5β-THP were found to be significantly higher in patients with fatigue ( P  < 0.05), while those of patients without fatigue were not significantly different from controls. Both 3α,5α-THP and 3α,5β-THP are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA-A) receptor and readily cross the blood–brain barrier. The present preliminary findings suggest that increased inhibition through GABA-A receptors due to the accumulation of neuroinhibitory steroids may represent an important pathophysiological mechanism of fatigue in chronic liver diseases.     

Oxidative stress and inflammation mediate the effect of air pollution on cardio‐ and cerebrovascular disease: A prospective study in nonsmokers

Air pollution is associated with a broad range of adverse health effects, including mortality and morbidity due to cardio‐ and cerebrovascular diseases (CCVD), but the molecular mechanisms involved are not entirely understood. This study aims to investigate the involvement of oxidative stress and inflammation in the causal chain, and to identify intermediate biomarkers that are associated retrospectively with the exposure and prospectively with the disease. We designed a case‐control study on CCVD nested in a cohort of 18,982 individuals from the EPIC‐Italy study. We measured air pollution, inflammatory biomarkers, and whole‐genome DNA methylation in blood collected up to 17 years before the diagnosis. The study sample includes all the incident CCVD cases among former‐ and never‐smokers, with available stored blood sample, that arose in the cohort during the follow‐up. We identified enrichment of altered DNA methylation in “ROS/Glutathione/Cytotoxic granules” and “Cytokine signaling” pathways related genes, associated with both air pollution (multiple comparisons adjusted p for enrichment ranging from 0.01 to 0.03 depending on pollutant) and with CCVD risk (P = 0.04 and P = 0.03, respectively). Also, Interleukin‐17 was associated with higher exposure to NO₂ (P = 0.0004), NO_x (P = 0.0005), and CCVD risk (OR = 1.79; CI 1.04–3.11; P = 0.04 comparing extreme tertiles). Our findings indicate that chronic exposure to air pollution can lead to oxidative stress, which in turn activates a cascade of inflammatory responses mainly involving the “Cytokine signaling” pathway, leading to increased risk of CCVD. Inflammatory proteins and DNA methylation alterations can be detected several years before CCVD diagnosis in blood samples, being promising preclinical biomarkers. Environ. Mol. Mutagen. 59:234–246, 2018. © 2017 Wiley Periodicals, Inc.