WldS Reduces Paraquat-Induced Cytotoxicity via SIRT1 in Non-Neuronal Cells by Attenuating the Depletion of NAD

WldS is a fusion protein with NAD synthesis activity, and has been reported to protect axonal and synaptic compartments of neurons from various mechanical, genetic and chemical insults. However, whether WldS can protect non-neuronal cells against toxic chemicals is largely unknown. Here we found that WldS significantly reduced the cytotoxicity of bipyridylium herbicides paraquat and diquat in mouse embryonic fibroblasts, but had no effect on the cytotoxicity induced by chromium (VI), hydrogen peroxide, etoposide, tunicamycin or brefeldin A. WldS also slowed down the death of mice induced by intraperitoneal injection of paraquat. Further studies demonstrated that WldS markedly attenuated mitochondrial injury including disruption of mitochondrial membrane potential, structural damage and decline of ATP induced by paraquat. Disruption of the NAD synthesis activity of WldS by an H112A or F116S point mutation resulted in loss of its protective function against paraquat-induced cell death. Furthermore, WldS delayed the decrease of intracellular NAD levels induced by paraquat. Similarly, treatment with NAD or its precursor nicotinamide mononucleotide attenuated paraquat-induced cytotoxicity and decline of ATP and NAD levels. In addition, we showed that SIRT1 was required for both exogenous NAD and WldS-mediated cellular protection against paraquat. These findings suggest that NAD and SIRT1 mediate the protective function of WldS against the cytotoxicity induced by paraquat, which provides new clues for the mechanisms underlying the protective function of WldS in both neuronal and non-neuronal cells, and implies that attenuation of NAD depletion may be effective to alleviate paraquat poisoning

Primary progressive aphasia: a clinical approach

This work was supported by the Alzheimer’s Society (AS-PG-16-007), the National Institute for Health Research University College London Hospitals Biomedical Research Centre and the UCL Leonard Wolfson Experimental Neurology Centre (PR/ylr/18575). Individual authors were supported by the Leonard Wolfson Foundation (Clinical Research Fellowship to CRM), the National Institute for Health Research (NIHR Doctoral Training Fellowship to AV), the National Brain Appeal–Frontotemporal Dementia Research Fund (CNC) and the Medical Research Council (PhD Studentships to CJDH and RLB, MRC Research Training Fellowship to PDF, MRC Clinician Scientist to JDR). MNR and NCF are NIHR Senior Investigators. SJC is supported by Grants from ESRC-NIHR (ES/L001810/1), EPSRC (EP/M006093/1) and Wellcome Trust (200783). JDW was supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (091673/Z/10/Z)

Frontal Plane Knee Mechanics and Early Cartilage Degeneration in People With Anterior Cruciate Ligament Reconstruction: A Longitudinal Study

BackgroundAbnormal frontal plane gait mechanics are known risk factors for knee osteoarthritis, but their role in early cartilage degeneration after anterior cruciate ligament reconstruction (ACLR) is not well understood. Hypothesis/Purpose: The objective was to evaluate the association of frontal plane gait mechanics with medial knee cartilage magnetic resonance (MR) relaxation times over 1 year in patients with ACLR and controls. It was hypothesized that (1) there will be an increase in frontal plane medial knee loading and medial knee MR relaxation times over time in the patients with ACLR, and (2) increases in frontal plane medial knee loading will be associated with an increase in medial knee MR relaxation times.Study designCase-control study; Level of evidence, 3.MethodsPatients with ACLR (n = 37) underwent walking gait analyses and bilateral quantitative MR imaging (MRI) before surgery and at 6 and 12 months after ACLR. Healthy control participants (n = 13) were evaluated at baseline and 12 months. Gait variables included peak knee adduction moment (KAM), KAM impulse, and peak knee adduction angle. MRI variables included medial femur and medial tibia whole compartment and subregional T1ρ and T2 relaxation times. Statistical analyses included a comparison of changes over time for gait and MRI variables, correlations between changes in gait and MRI variables over time, and differences in change in MRI variables in patients who showed an increase versus decrease in KAM impulse.ResultsThere were significant increases in medial T1ρ (Δ 4%-11%) and T2 (Δ 2%-10%) relaxation times from baseline to 6 months for both knees in the ACLR group and in KAM (Δ 13%) for the injured knee. From baseline to 6 months, patients who had an increase in KAM impulse in the injured knee had a greater increase in medial T1ρ and T2 relaxation times as compared with those who did not have an increase in KAM impulse. Longitudinal changes for the control group were not significant.ConclusionThere is an increase in medial knee relaxation times over the first 6 months after ACLR. People with an increase in medial knee loading show an increase in medial knee relaxation times when compared with those who do not have an increase in medial knee loading over the first 6 months