Nrf2 attenuates the innate immune response after experimental myocardial infarction.

BACKGROUND: There is compelling evidence implicating dysregulated inflammation in the mechanism of ventricular remodeling and heart failure (HF) after MI. The transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2, encoded by Nfe2l2) is a promising target in this context since it impedes transcriptional upregulation of pro-inflammatory cytokines and is anti-inflammatory in various murine models. OBJECTIVES: We aimed to investigate the contribution of Nrf2 to the inflammatory response after experimental myocardial infarction (MI). METHODS: We subjected Nrf2-/- mice and wild type (WT) controls to permanent left coronary artery (LCA) ligation. The inflammatory response was investigated with fluorescence-activated cell sorting (FACS) analysis of peripheral blood and heart cell suspensions, together with qRT-PCR of infarcted tissue for chemokines and their receptors. To investigate whether Nrf2-mediated transcription is a dedicated function of leukocytes, we interrogated publicly available RNA-sequencing (RNA-seq) data from mouse hearts after permanent LCA ligation for Nrf2-regulated gene (NRG) expression. RESULTS: FACS analysis demonstrated a profoundly inflamed phenotype in the hearts of global Nrf2-/- mice as compared to WT mice after MI. Moreover, infarcted tissue from Nrf2-/- mice displayed higher expression of mRNA coding for inflammatory cytokines, chemokines, and their receptors, including IL-6, Ccl2, and Cxcr4. RNA-seq analysis showed upregulated NRG expression in WT mice after MI compared to naive mice, which was significantly higher in bioinformatically isolated CCR2+ cells. CONCLUSIONS: Taken together, the results suggest that Nrf2 signalling in leukocytes, and possibly CCR2+ monocytes and monocyte-derived cardiac resident macrophages, may be potential targets to prevent post-MI ventricular remodeling.

Cognitive impairment and development of dementia in very late-onset schizophrenia-like psychosis: a systematic review.

OBJECTIVES: This study aimed to review the evidence base regarding cognitive impairment and the development of dementia in patients with very late-onset schizophrenia-like psychosis (VLOSLP). METHODS: We conducted a systematic literature search of PubMed, PsycINFO and Web of Science according to Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. Two reviewers independently screened records first by title and abstract and then by full text, resolving differences after each stage. Selected studies were assessed for quality using the GRADE system, and data on study design, participants, cognitive ability and rates of developing dementia were extracted and synthesised. RESULTS: Seventeen publications were identified for review. They were generally poor in quality and heterogenous in design. VLOSLP patients were found to have impaired global cognition compared to non-psychotic controls, but no difference was found between VLOSLP patients and aged early-onset schizophrenia (EOS) patients. No single cognitive domain was consistently affected. Patients with VLOSLP demonstrated significantly higher rates of dementia diagnosis (ranging from 4.4% over 3 years to 44.4% over 15 years) than controls, but no difference was found between VLOSLP patients and aged EOS patients. CONCLUSIONS: VLOSLP may not necessarily predict cognitive decline, but few studies have adequately investigated cohorts on a longitudinal basis. Heterogeneity between and within cohorts and varying selection criteria compromise the clinical generalisability of studies investigating the association between VLOSLP and neurodegenerative disease. Further studies on the clinical presentation, cognitive profile and neuropathology of VLOSLP with comparison to EOS/late-onset schizophrenia (LOS) and neurodegenerative disease are needed to better inform the diagnosis and management of VLOSLP.