Nicotinamide Riboside Augments Human Macrophage Migration via SIRT3-Mediated Prostaglandin E2 Signaling.

NAD+ boosting via nicotinamide riboside (NR) confers anti-inflammatory effects. However, its underlying mechanisms and therapeutic potential remain incompletely defined. Here, we showed that NR increased the expression of CC-chemokine receptor 7 (CCR7) in human M1 macrophages by flow cytometric analysis of cell surface receptors. Consequently, chemokine ligand 19 (CCL19, ligand for CCR7)-induced macrophage migration was enhanced following NR administration. Metabolomics analysis revealed that prostaglandin E2 (PGE2) was increased by NR in human monocytes and in human serum following in vivo NR supplementation. Furthermore, NR-mediated upregulation of macrophage migration through CCL19/CCR7 was dependent on PGE2 synthesis. We also demonstrated that NR upregulated PGE2 synthesis through SIRT3-dependent post-transcriptional regulation of cyclooxygenase 2 (COX-2). The NR/SIRT3/migration axis was further validated using the scratch-test model where NR and SIRT3 promoted more robust migration across a uniformly disrupted macrophage monolayer. Thus, NR-mediated metabolic regulation of macrophage migration and wound healing may have therapeutic potential for the topical management of chronic wound healing.

Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes.

BACKGROUNDFasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODSWe explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE).RESULTSRNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-ß production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that NAD+ is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-ß release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-ß release.CONCLUSIONWe conclude that NR, in an NAD+-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management.TRIAL REGISTRATIONClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372.FUNDINGThis work was supported by the NHLBI and NIAMS Intramural Research divisions.

Right Mini-Thoracotomy for Aortic Plus Mitral with or without Tricuspid Valve Surgery.

OBJECTIVES: Minimally invasive surgery is increasingly performed for isolated aortic or mitral valve procedures. However, combined minimally invasive aortic and mitral valve surgery is rare. We report our initial experience performing multiple valve procedures through a right-sided mini-thoracotomy (RMT) compared with sternotomy. METHODS: A total of 264 patients underwent aortic and mitral with or without tricuspid valve surgery through RMT (n = 25) or sternotomy (n = 239). Propensity score matching was used for outcome comparisons. RESULTS: Of the 264 patients, 25 (age: 72 ± 10 years; 72% male) underwent double (n = 19) and triple valve surgery (n = 6) through RMT and 239 (age: 71 ± 11 years; 54% male) underwent double (n = 176) and triple valve surgery (n = 63) through sternotomy. Sternotomy patients had more co-morbidities and preoperative risk factors (EuroSCORE II 10.25 ± 10.89 vs. RMT 3.58. ± 4.98; p < 0.001). RMT procedures were uneventful without intraoperative complications or conversions to sternotomy. After propensity score matching, surgical procedures were comparable between groups with a higher valve repair rate in RMT. Despite longer cardiopulmonary bypass times in RMT, there was no evidence for differences in 30-day mortality (RMT: n = 2 vs. sternotomy: n = 2) and there were no significant differences in other outcomes. During 5-year follow-up, reoperation was required in sternotomy patients only (n = 2). Follow-up echocardiography showed durable results after valve surgery. RMT patients showed higher survival probability compared with sternotomy, although this difference was not significant (hazard ratio = 0.33; 95% confidence interval: 0.06-1.65; p = 0.18). CONCLUSION: Combined aortic plus mitral with or without tricuspid valve surgery can safely be performed through a RMT with a trend toward better mid-term outcomes.