New therapeutics for the prevention or amelioration of fetal alcohol spectrum disorders: a narrative review of the preclinical literature.

Background: Ethanol consumption during pregnancy induces enduring detrimental effects in the offspring, manifesting as a spectrum of symptoms collectively termed as Fetal Alcohol Spectrum Disorders (FASD). Presently, there is a scarcity of treatments for FASD.Objectives: To analyze current literature, emphasizing evidence derived from preclinical models, that could potentially inform therapeutic interventions for FASD.Methods: A narrative review was conducted focusing on four prospective treatments: nutritional supplements, antioxidants, anti-inflammatory compounds and environmental enrichment. The review also highlights innovative therapeutic strategies applied during early (e.g. folate administration, postnatal days 4-9) or late (e.g. NOX2 inhibitors given after weaning) postnatal stages that resulted in significant improvements in behavioral responses during adolescence (a critical period marked by the emergence of mental health issues in humans).Results: Our findings underscore the value of treatments centered around nutritional supplementation or environmental enrichment, aimed at mitigating oxidative stress and inflammation, implying shared mechanisms in FASD pathogenesis. Moreover, the review spotlights emerging evidence pertaining to the involvement of novel molecular components with potential pharmacological targets (such as NOX2, MCP1/CCR2, PPARJ, and PDE1).Conclusions: Preclinical studies have identified oxidative imbalance and neuroinflammation as relevant pathological mechanisms induced by prenatal ethanol exposure. The relevance of these mechanisms, which exhibit positive feedback loop mechanisms, appear to peak during early development and decreases in adulthood. These findings provide a framework for the future development of therapeutic avenues in the development of specific clinical treatments for FASD.

Effect of plasma exchange with albumin replacement on albumin functionality and organ dysfunction in acute-on-chronic liver failure.

Background & Aims: Effective treatments for acute-on-chronic liver failure (ACLF) are a major unmet need. This proof-of-concept pilot study was aimed at evaluating the effects of plasma exchange (PE) with albumin 5% (PE-A5%) on albumin functional capacity and organ dysfunction in patients with ACLF. Methods: Ten adult patients were enrolled in a single-center phase II, prospective, open-label, non-controlled study. Six PE-A5% sessions were performed in 10 days followed by a 1-month follow-up visit. Albumin functional capacity and circulatory function were assessed, as were renal, cerebral, and liver function, and systemic inflammation. The main safety variable was the percentage of PE sessions associated with at least one procedure-related adverse event (AE). Results: Patients with ACLF showed lower albumin binding capacity, lower antioxidant capacity, and lower levels of albumin with preserved structure compared to healthy donors (n = 19). From baseline to day 11, PE-A5% treatment increased albumin levels and improved albumin binding capacity to Sudlow site II (15.3±1.6 mg/ml to 18.9±1.7 mg/ml; p = 0.003), fatty acid-binding capacity (8.2±1.4 µM to 3.1±1.5 µM; p = 0.013) and antioxidant capacity (human mercaptalbumin 9.5±1.5 mg/ml to 14.6±1.6 mg/ml; p = 0.001). Native albumin levels were increased throughout day 1-11 PE-A5% sessions (6.5±1.0 mg/ml to 10.2±1.4 mg/ml; p = 0.035). PE-A5% improved systemic hemodynamics (mean arterial pressure, heart rate, cardiac index), renal function (creatinine level, blood urea nitrogen), cerebral function (hepatic encephalopathy grade), liver parameters (transaminases, bilirubin) and inflammatory parameters (C-reactive protein, leukocyte count). All patients had at least one of the 78 AEs reported, mostly mild (product/procedure-related: 36%). Sixteen serious AEs were reported in eight patients (procedure/product-related: none). Conclusions: PE-A5% was a safe procedure associated with positive effects on albumin functionality, and circulatory, renal, cerebral, and liver function in patients with ACLF. Impact and implications: Acute-on-chronic liver failure (ACLF) is a clinical condition characterized by severe systemic inflammation, organ failure, and high mortality. Plasma exchange removes patient's plasma containing pathogenic substances, replacing it with 5% albumin and fresh frozen plasma (PE-A5%). In this study, cirrhotic patients with ACLF were treated with PE-A5%, which was a safe procedure that increased binding and antioxidant capacity of patients' albumin, while improving circulatory, kidney, brain, and liver functions. These beneficial effects could impact survival in ACLF. ClinicalTrialsgov Identifier: NCT01201720. EudraCT number: 2010-021360-15.

Evolution of lysine-specific demethylase 1 and REST corepressor gene families and their molecular interaction.

Lysine-specific demethylase 1A (LSD1) binds to the REST corepressor (RCOR) protein family of corepressors to erase transcriptionally active marks on histones. Functional diversity in these complexes depends on the type of RCOR included, which modulates the catalytic activity of the complex. Here, we studied the duplicative history of the RCOR and LSD gene families and analyzed the evolution of their interaction. We found that RCOR genes are the product of the two rounds of whole-genome duplications that occurred early in vertebrate evolution. In contrast, the origin of the LSD genes traces back before to the divergence of animals and plants. Using bioinformatics tools, we show that the RCOR and LSD1 interaction precedes the RCOR repertoire expansion that occurred in the last common ancestor of jawed vertebrates. Overall, we trace LSD1-RCOR complex evolution and propose that animal non-model species offer advantages in addressing questions about the molecular biology of this epigenetic complex.