Graphical abstract

Abstract

Rett syndrome (RTT), a monogenic neurodevelopmental disorder mainly affecting female, is caused by mutations in X-linked MECP2 gene, an ubiquitous epigenetic regulator. In addition to neurological issues, RTT patients show a variety of multisystem manifestations and impairment of different signalling and metabolic pathways, including compromised mitochondrial function, altered redox homeostasis, improper cholesterol metabolism and subclinical inflammation. The sirtuin family (SIRTs), comprising seven members, catalyses the NAD⁺-dependent deacetylation, ADP-ribosylation and deacylation of a wide range of targets and works as sensors of cellular energetic status. In addition, SIRTs can modulate activities and gene expression of proteins involved in cellular stress responses related to oxidative stress, mitochondrial dysfunctions and inflammation, in both physiological and pathological conditions. Given some shared molecular aspects, herein, we revised the current scientific literature and hypothesized the possible relationship of SIRTs signalling involvement in RTT pathogenesis and OxInflammation. Although further research is needed, uncovering the possible involvement of SIRTs in RTT could reveal new potential pharmacological targets for the disorder. In light of this, SIRT-enhancing compounds could likely represent a new option to be tested as co-adjuvant alternatives to the current therapies.

Objective

Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress due to cigarette smoking seems to be one of the major driving mechanisms in COPD pathogenesis. Since the scavenger receptor B1 (SR-B1) appears to play a key role in mediating the uptake for ɑ-tocopherol and other antioxidants in lung tissue, we aimed to investigate its role in COPD pathogenesis.

Methods

Lung tissue biopsies were obtained from 12 subjects; 6 of these had a diagnosis of COPD in a stable clinical state, the others 6 were current (n = 1) or ex-smokers (n = 5) with normal lung function (controls). 4-Hydroxynonenal (4-HNE)–SR-B1 adducts were detected by immunoprecipitation. ɑ-tocopherol concentration was determined by HPLC.

Results

SR-B1 levels were lower in COPD patients and these results parallel with lower levels of vitamin E in lung tissue found in COPD patients. This effect can be the consequence of oxidative posttranslational modifications, confirmed by the binding of the peroxidation product 4-HNE to SR-B1 possibly leading to its degradation.

Conclusions

The loss of SR-B1 may be involved in lung ɑ-tocopherol content decrease with the consequence of making lung tissue more susceptible to oxidative damage as suggested by the SR-B1–4-HNE adduct formation, and more prone to COPD development. Thus, our findings suggest a novel role of SR-B1 in pathomechanisms underlying COPD.

Significance statement

Chronic obstructive pulmonary disease (COPD) is one of the main causes of morbidity and mortality in the United States. Oxidative stress has been suggested to be the major driving mechanism in COPD pathogenesis. Loss of scavenger receptor BI (SR-B1) significantly decreases tocopherol lung content making lung tissue more susceptible to oxidative damage. The results of our study show that SR-B1 levels were lower in COPD patients and these results parallel with lower levels of vitamin E in lung tissue. Our findings suggest a novel role of SR- B1 in pathomechanisms underlying COPD.