ABSTRACT
OBJECTIVES: Cellular NAD+ declines in inflammatory states associated with increased activity of the leukocyte-expressed NADase CD38. In this study, we tested the potential role of therapeutically targeting CD38 and NAD+ in gout. METHODS: We studied cultured mouse wild type and CD38 knockout (KO) murine bone marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals and used the air pouch gouty inflammation model. RESULTS: MSU crystals induced CD38 in BMDMs in vitro, associated with NAD+ depletion, and IL-1ß and CXCL1 release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 inflammasome activation and increased anti-inflammatory SIRT3-SOD2 activity in macrophages. BMDM RNA-seq analysis of differentially expressed genes (DEGs) revealed CD38 to control multiple MSU crystal-modulated inflammation pathways. Top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-κB activation when it is overexpressed. CONCLUSIONS: CD38 and NAD+ depletion are druggable targets controlling the MSU crystal- induced inflammation program. Targeting CD38 and NAD+ are potentially novel selective molecular approaches to limit gouty arthritis.
Subject(s)
ADP-ribosyl Cyclase 1 , Inflammation , Macrophages , Mice, Inbred C57BL , Mice, Knockout , NAD , Uric Acid , Animals , ADP-ribosyl Cyclase 1/genetics , ADP-ribosyl Cyclase 1/metabolism , Macrophages/drug effects , Macrophages/metabolism , Inflammation/drug therapy , Mice , NAD/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Male , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Cells, Cultured , Arthritis, Gouty/drug therapy , Arthritis, Gouty/metabolism , Arthritis, Gouty/genetics , Inflammasomes/metabolism , Inflammasomes/drug effectsABSTRACT
SARS-CoV-2 has resulted in high levels of morbidity and mortality world-wide, and severe complications can occur in older populations. Humoral immunity induced by authorized vaccines wanes within 6 months, and frequent boosts may only offer transient protection. GRT-R910 is an investigational self-amplifying mRNA (samRNA)-based SARS-CoV-2 vaccine delivering full-length Spike and selected conserved non-Spike T cell epitopes. This study reports interim analyses for a phase I open-label dose-escalation trial evaluating GRT-R910 in previously vaccinated healthy older adults (NCT05148962). Primary endpoints of safety and tolerability were assessed. Most solicited local and systemic adverse events (AEs) following GRT-R910 dosing were mild to moderate and transient, and no treatment-related serious AEs were observed. The secondary endpoint of immunogenicity was assessed via IgG binding assays, neutralization assays, interferon-gamma ELISpot, and intracellular cytokine staining. Neutralizing antibody titers against ancestral Spike and variants of concern were boosted or induced by GRT-R910 and, contrasting to authorized vaccines, persisted through at least 6 months after the booster dose. GRT-R910 increased and/or broadened functional Spike-specific T cell responses and primed functional T cell responses to conserved non-Spike epitopes. This study is limited due to small sample size, and additional data from ongoing studies will be required to corroborate these interim findings.
Subject(s)
COVID-19 , RNA, Messenger/genetics , COVID-19/prevention & control , Humans , Aged , Male , Female , Middle Aged , Aged, 80 and over , Clinical Trials as Topic , Antibodies, Viral/immunology , Antibodies, Neutralizing/immunology , T-Lymphocytes/immunologyABSTRACT
After reconstruction, the return to full competition rate of athletes is low, while the re-injury rate remains high despite the completion of a rehabilitation programme. Primary ACL prevention programmes are well developed, yet few research papers focus on secondary ACL injury prevention. The aim of current review is to determine if current ACL secondary prevention training has a positive influence on the re-injury rate, the clinical or functional outcomes, or the risk of re-injury in athletes. Studies investigating secondary prevention of ACL were searched in PubMed and EBSCOhost, followed by a review of the references in the identified articles. The existing evidence suggests that neuromuscular training, eccentric strengthening, and plyometric exercises may have a potential impact on improving biomechanical, functional, and psychological outcomes in athletes; however, the studies on the prevention of second ACL injury in athletes is scarce and inconclusive. Future research is needed to investigate the effectiveness of secondary ACL prevention in reducing the re-injury rates. (PROSPERO Registration number: CRD42021291308).