Summary Tyrosyl-tRNA synthetase (TyrRS) is known for its essential aminoacylation function in protein synthesis. Here we report a new function for TyrRS in DNA damage protection. We found that oxidative stress, which often down-regulates protein synthesis, induces TyrRS to rapidly translocate from the cytosol to the nucleus. We also found that angiogenin mediates or potentiates this stress-induced translocalization. The nuclear-localized TyrRS activates transcription factor E2F1 to up-regulate the expression of DNA damage repair genes such as BRCA1 and RAD51. The activation is achieved through direct interaction of TyrRS with TRIM28 to sequester this vertebrate-specific epigenetic repressors and its associated HDAC1 from deacetylating and suppressing E2F1. Remarkably, overexpression of TyrRS strongly protects against UV-induced DNA double-strand breaks in zebrafish, while restricting TyrRS nuclear entry completely abolishes the protection. Therefore, oxidative stress triggers an essential cytoplasmic enzyme used for protein synthesis to translocate to the nucleus to protect against DNA damage.

Hyperuricemia has been associated with chronic kidney disease (CKD) progression. The antihyperuricemic febuxostat's potential renoprotective effect has been demonstrated in stage 1-3 CKD. Large-scale studies comparing the renoprotective potential of febuxostat and allopurinol in advanced CKD are lacking. We exclusively selected 6,057 eligible patients with predialysis stage 5 CKD prescribed either febuxostat or allopurinol using the National Health Insurance Research Database in Taiwan during 2012-2015. There were 69.57% of allopurinol users and 42.01% febuxostat users who required long-term dialysis (P < 0.0001). The adjusted hazard ratio (HR) of 0.65 (95% confidence interval (CI) 0.60-0.70) indicated near 35% lower hazards of long-term dialysis with febuxostat use. The renal benefit of febuxostat was consistent across most patient subgroups and/or using the propensity score-matched cohort. The adjusted HR was 0.66 (95% CI, 0.61-0.70) for long-term dialysis or death. In conclusion, lower risk of progression to dialysis was observed in predialysis stage 5 CKD febuxostat users without compromising survival.

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

BackgroundAdvanced chronic kidney disease (CKD) patients are at higher risk of sepsis-related mortality following infection and bacteremia. Interestingly, the urate-lowering febuxostat and allopurinol, both xanthine oxidase inhibitors (XOis), have been suggested to influence the sepsis course in animal studies. In this study, we aim to investigate the relationship between XOis and infection/sepsis risk in pre-dialysis population.MethodsPre-dialysis stage 5 CKD patients with gout were identified through the National Health Insurance Research Database (NHIRD) in Taiwan from 2012 to 2016. Outcomes were also compared with national data.ResultsIn our nationwide, population-based cohort study, 12,786 eligible pre-dialysis stage 5 CKD patients were enrolled. Compared to non-users, febuxostat users and allopurinol users were associated with reduced sepsis/infection risk [hazard ratio (HR), 0.93; 95% confidence interval (CI), 0.87–0.99; P = 0.0324 vs. HR, 0.92; 95% CI, 0.86–0.99; P = 0.0163]. Significant sepsis/infection-related mortality risk reduction was associated with febuxostat use (HR, 0.68; 95% CI, 0.52–0.87). Subgroup analysis demonstrated preference of febuxostat over allopurinol in sepsis/infection-related mortality among patients younger than 65 years of age, stain users, non-steroidal anti-inflammatory drug non-users, and non-diabetics. There was no significant difference in major adverse cardiac and cerebrovascular event (MACCE) risk between users and non-users while reduced risk of all-cause mortality was observed for XOi users.ConclusionsUse of XOi in pre-dialysis stage 5 CKD patients may be associated with reduced risk of sepsis/infection and their related mortality without increased MACCE and overall mortality.