: Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.

Background: Few studies have investigated the influence of body mass index (BMI) trajectories on lung function covering the entire growth period.Methods: We conducted a prospective study using data from the Swedish BAMSE birth cohort. Latent class mixture modelling was employed to examine the diversity in BMI z-scores from birth to 24 years of age. Participants with four or more BMI z-scores were included (n=3204, 78.4%). Pre-bronchodilator spirometry was tested at 8, 16 and 24 years, while post-bronchodilator spirometry, multiple-breath nitrogen washout (for lung clearance index) and urinary metabolomics data were assessed at 24 years.Results: Six distinct BMI development groups were identified. Compared to the stable normal BMI group, the accelerated increasing BMI group exhibited reduced pre- and post-bronchodilator forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) ratio z-scores (pre: β= −0.26, 95% CI −0.44– −0.08; post: β= −0.22, 95% CI −0.39– −0.05), along with elevated lung clearance index (0.30, 95% CI 0.22–0.42) at 24 years. The persistent high BMI group demonstrated lower FEV₁(−0.24, 95% CI −0.42– −0.05) and FVC (−0.27, 95% CI −0.45– −0.01) z-score growth between 16 and 24 years, and elevated lung clearance index (0.20, 95% CI 0.03–0.39) at 24 years. However, those impairments were not observed in the accelerated resolving BMI group. Conversely, the persistent low BMI group displayed persistently decreased FEV₁and FVC from 8 to 24 years, as well as decreased lung function growth. Additionally, histidine-related metabolites were associated with pre- and post-bronchodilator FEV₁(hypergeometric false discovery rate=0.008 and <0.001, respectively).Conclusions: Early interventions aiming for normal BMI during childhood may contribute to improved lung health later in life.

The chemical burden on the environment and human population is increasing. Consequently, regulatory risk assessment must keep pace to manage, reduce, and prevent adverse impacts on human and environmental health associated with hazardous chemicals. Surveillance of chemicals of known, emerging, or potential future concern, entering the environment-food-human continuum is needed to document the reality of risks posed by chemicals on ecosystem and human health from a one health perspective, feed into early warning systems and support public policies for exposure mitigation provisions and safe and sustainable by design strategies. The use of less-conventional sampling strategies and integration of full-scan, high-resolution mass spectrometry and effect-directed analysis in environmental and human monitoring programmes have the potential to enhance the screening and identification of a wider range of chemicals of known, emerging or potential future concern. Here, we outline the key needs and recommendations identified within the European Partnership for Assessment of Risks from Chemicals (PARC) project for leveraging these innovative methodologies to support the development of next-generation chemical risk assessment.

Purpose: To examine the effects of low-dose exposure to uranium with a systems biology approach, a multiscale high-throughput multi-omics analysis was applied with a protocol for chronic exposure to the rat kidney. Methods: Male and female rats were contaminated for nine months through their drinking water with a nontoxic solution of uranyl nitrate. A multiscale approach enabled clinical monitoring associated with metabolomic and transcriptomic (mRNA and microRNA) analyses. Results: A sex-interaction effect was observed in the kidney, urine, and plasma metabolomes of contaminated rats. Moreover, urine and kidney metabolic profiles correlated and confirmed that the primary dysregulated metabolisms are those of nicotinate-nicotinamide and of unsaturated fatty acid biosynthesis. Upstream of the metabolic pathways, transcriptomic profiles of the kidney reveal gene activity focused on gene regulation mechanisms, cell signaling, cell structure, developmental processes, and cell proliferation. Examination of epigenetic post-transcriptional gene regulation processes showed significant dysregulation of 70 micro-RNAs. The multi-omics approach highlighted the activities of the cells' biological processes on multiple scales through analysis of gene expression, confirmed by changes observed in the metabolome. Conclusion: Our results showed changes in multi-omic profiles of rats exposed to low doses of uranium contamination, compared with controls. These changes involved gene expression as well as modifications in the transcriptome and the metabolome. The metabolomic profile confirmed that the main molecular targets of uranium in kidney cells are the metabolism of nicotinate-nicotinamide and the biosynthesis of unsaturated fatty acids. Additionally, gene expression analysis showed that the metabolism of fatty acids is targeted by processes associated with cell function. These results demonstrate that multiscale systems biology is useful in elucidating the most discriminative pathways from genomic to metabolomic levels for assessing the biological impact of this low-level environmental exposure, i.e. the exposome.