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Aims Delphinidin (DEL) is a plant-derived antioxidant with clinical potential to treat inflammatory pain but suffers from poor solubility and low bioavailability. GW5074 The aim of the study was to develop a well-tolerated cyclodextrin (CD)-DEL complex with enhanced bioavailability and to investigate the mechanisms behind its antinociceptive effects in a preclinical model of inflammatory pain. Results CD-DEL was highly soluble and stable in aqueous solution, and was nontoxic. Systemic administration of CD-DEL reversed mechanical and heat hyperalgesia, while its local application into the complete Freund's adjuvant (CFA)-induced inflamed paw dose-dependently reduced mechanical hyperalgesia, paw volume, formation of the lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE), and tissue migration of CD68+ macrophages. CD-DEL also directly prevented 4-HNE-induced mechanical hyperalgesia, cold allodynia, and an increase in the intracellular calcium concentration into transient receptor potential ankyrin 1 expressing cells. Both 4-HNE- and CFA-induced reactive oxygen species (ROS) levels were sensitive to CD-DEL, while its capacity to scavenge superoxide anion radicals (inhibitory concentration 50 [IC50] 70 ± 5 μM) was higher than that observed for hydroxyl radicals (IC50 600 ± 50 μM). Finally, CD-DEL upregulated heme oxygenase 1 that was prevented by HMOX-1 siRNA in vitro. Innovation In vivo application of DEL to treat inflammatory pain is facilitated by complexation with CD. Apart from its antioxidant effects, the CD-DEL has a unique second antioxidative mechanism involving capturing of 4-HNE into the CD cavity followed by displacement and release of the ROS scavenger DEL. Conclusion CD-DEL has antinociceptive, antioxidative, and anti-inflammatory effects making it a promising formulation for the local treatment of inflammatory pain.Gradually, bacteria have acquired resistance to antibiotics, predicting a slow but certain return to the preantibiotic era that may bring communicable diseases back as the leading cause of death and, additionally, severely affect the health care system. Based on current development, after a few decades, we may lack functional antibiotics for clinical treatments, emphasizing an urgent need to have alternatives, such as new classes of antimicrobial drugs, improved germ-free protocols, elimination of any kind of contamination in the surgery room, improved robotic surgeries, and novel noninvasive interventions. This forum discusses recent advances in the field of microbial defense mechanisms. Antioxid. Redox Signal. 34, 439-441.Theses reviewed in this issue include "Engineering Efficient and Safe In Situ Genome Regulation via CRISPR-Cas9 for Enabling Gene Therapies," "Investigating the Mechanism of LINE-1 Retrotransposition in Human Cells," "Machine Learning Approaches for Prediction of Kidney Transplant Survival," "Novel Obesity Suppressor Function of the Retinoblastoma Protein Uncovers Cyclin-Dependent Kinase 4 as a Therapeutic Target for Diet-Induced Obesity," "Regeneration of Retinal Neurons from Müller Glia in Adult Mice," and "Reprogramming T Cells to Interrogate Intracellular Disease Signatures."Restoration of correct splicing of βIVS2-654-globin pre-mRNA was previously accomplished in erythroid cells from β-thalassemia/HbE patients by an engineered U7 small nuclear RNA (snRNA) that carried a sequence targeted to the cryptic branch point and an exonic splicing enhancer, U7.BP+623 snRNA. In this study, this approach was tested in thalassemic mice carrying the βIVS2-654 mutation. While correction of βIVS2-654 pre-mRNA splicing was achieved in erythroid progenitors transduced with a lentiviral vector carrying the U7.BP+623 snRNA, a high level of truncated U7.BP+623 snRNA was also observed. The discrepancy of processing of the modified U7 snRNA in human and mouse constructs hamper the evaluation of pathologic improvement in mouse model.We questioned whether changes in high-intensity locomotor and micro-movements patterns between the first and second part of each half depend on playing position in the 2014-2015 European rugby union championship winning team. Thirty-three rugby players were grouped according to five playing positions. Players were equipped with micro-electromechanical system including a GPS sampling at 10 Hz and high temporal resolution micro-sensors during 17 Top14 and 7 European games. High-speed movements (HSM), high-intensity accelerations (HIA), repeated high-intensity efforts (RHIE), and high-intensity micro-movements (HIMM) were subsequently compared between four 20-min game periods. No significant group × time interactions were observed for any locomotor variables (p > 0.283). Irrespectively of playing position, the number of HSM (p = 0.019), decreased from 0-20 min to 60-80 min as well as from 40-60 to 60-80 min (p  less then  0.001) with HIA (p = 0.020) and RHIE (p  less then  0.001). Significant group × time interaction was found for HIMM (p = 0.03) with a significant decrease observed in back row forwards from 0-20 to 60-80 min periods (-17.5%; ES = 0.6; p = 0.031). In elite rugby union, fatigue-induced changes during the last 20 min are independent from playing positions in high-intensity locomotor patterns in contrary to HIMM. Training drills that include specific RHIE (high-speed and HIA efforts) may be useful to postpone match-related fatigue. Highlights Fatigue-induced changes during the last 20 min are independent from playing positions in high-intensity locomotor patterns. Training drills that include specific repeated high-intensity efforts may be useful to postpone matchrelated fatigue.Introduction To compare surgical, oncologic, functional outcomes and complication rate between intracorporeal neobladder (ICNB) and extracorporeal neobladder (ECNB) orthotopic ileal neobladder of robot-assisted radical cystectomy (RARC) in patients with nonmetastatic bladder carcinoma (BC). Materials and Methods From 2014 to 2019, we prospectively collected and retrospectively analyzed 101 patients with nonmetastatic BC treated with RARC and ortothopic neobladder. Chi-squared test estimated differences in proportions of functional and oncologic outcomes. Multivariable logistic regression models (MLRMs) focused on overall, early (30 days from discharge) in ICNB vs ECNB. Results Of all patients, 57 (56.4%) ICNB and 44 (43.6%) ECNB patients were identified. At least one complication occurred in 75.4% vs 72.7% in ICNB vs ECNB, respectively (p = 0.9). In MLRMs, focusing on complication rate, there was no statistically significant difference between ICNB vs ECNB for overall (p = 0.8), early (p = 0.6), and late complications (p = 0.
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