Mechanistic and Kinetic Insights into Cellular Uptake of Biomimetic Dinitrosyl Iron Complexes and Intracellular Delivery of NO for Activation of Cytoprotective HO-1.

Dinitrosyl iron unit (DNIU), [Fe(NO)2], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO)2Fe(µ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) and [(NO)2Fe(µ-SCH2CH2COOCH3)2Fe(NO)2] (DNIC-COOMe) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway (tmax = 0.5 h), intracellular assembly of mononuclear DNIC [(NO)2Fe(SR)(SCys)]n-/[(NO)2Fe(SR)(SCys-protein)]n- occurred, followed by O2-induced release of free NO (tmax = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis (tmax = 2-8 h) and for intracellular release of NO (tmax = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH/DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.

Does Surgery Reduce the Risk of Complications Among Patients with Multiple Rib Fractures? A Meta-analysis.

BACKGROUND: Multiple rib fractures are common in trauma patients, who are prone to trauma-associated complications. Surgical or nonsurgical interventions for the aforementioned conditions remain controversial. QUESTIONS/PURPOSES: The purpose of our study was to perform a meta-analysis to evaluate the clinical prognosis of surgical fixation of multiple rib fractures in terms of (1) hospital-related endpoints (including duration of mechanical ventilation, ICU length of stay [LOS] and hospital LOS), (2) complications, (3) pulmonary function, and (4) pain scores. METHODS: We screened PubMed, Embase, and Cochrane databases for randomized and prospective studies published before January 2018. Individual effect sizes were standardized; the pooled effect size was calculated using a random-effects model. Primary outcomes were duration of mechanical ventilation, intensive care unit length of stay (ICU LOS), and hospital LOS. Moreover, complications, pulmonary function, and pain were assessed. RESULTS: The surgical group had a reduced duration of mechanical ventilation (weighted mean difference [WMD], -4.95 days; 95% confidence interval [CI], -7.97 to -1.94; p = 0.001), ICU LOS (WMD, -4.81 days; 95% CI, -6.22 to -3.39; p < 0.001), and hospital LOS (WMD, -8.26 days; 95% CI, -11.73 to -4.79; p < 0.001) compared with the nonsurgical group. Complications likewise were less common in the surgical group, including pneumonia (odds ratio [OR], 0.41; 95% CI, 0.27-0.64; p < 0.001), mortality (OR, 0.24; 95% CI, 0.07-0.87; p = 0.030), chest wall deformity (OR, 0.02; 95% CI. 0.00-0.12; p < 0.001), dyspnea (OR, 0.23; 95% CI, 0.09-0.54; p < 0.001), chest wall tightness (OR, 0.11; 95% CI, 0.05-0.22; p < 0.001) and incidence of tracheostomy (OR, 0.34; 95% CI, 0.20-0.57; p < 0.001). There were no differences between the surgical and nonsurgical groups in terms of pulmonary function, such as forced vital capacity (WMD, 6.81%; 95% CI: -8.86 to 22.48; p = 0.390) and pain scores (WMD, -11.41; 95% CI: -42.09 to 19.26; p = 0.470). CONCLUSIONS: This meta-analysis lends stronger support to surgical fixation, rather than conservative treatment, for multiple rib fractures. Nevertheless, additional trials should be conducted to investigate surgical indications, timing, and followup for quality of life. LEVEL OF EVIDENCE: Level I, therapeutic study.