Activity

Hindered phenols preserved lysosomal integrity against ox-LDL-induced damage and FITC-labeled trolox was localized to the lysosomes in RPE cells. Analogs of trolox inhibited reactive oxygen species (ROS) formation induced by ox-LDL uptake in a dose-dependent fashion and were effective at sub-micromolar concentrations. Treatment with trolox analog 2,2,5,7,8-pentamethyl-6-chromanol (PMC) significantly induced the expression of the lysosomal protein NPC-1 and reduced intracellular cholesterol level upon ox-LDL uptake. Our data indicate that the lysosomal-localized hindered phenols are uniquely potent in protecting the RPE against the toxic effects of ox-LDL, and may represent a novel pharmacotherapy to preserve the vision in patients with GA.Receptor for activated C kinase 1 (RACK1) regulates various cellular functions and signaling pathways by interacting with different proteins. Recently, we showed that RACK1 interacts with breast cancer gene 1 (BRCA1), which regulates centrosome duplication. RACK1 localizes to centrosomes and spindle poles and is involved in the proper centrosomal localization of BRCA1. The interaction between RACK1 and BRCA1 is critical for the regulation of centrosome number. In addition, RACK1 contributes to centriole duplication by regulating polo-like kinase 1 (PLK1) activity in S phase. RACK1 binds directly to PLK1 and Aurora A, promoting the phosphorylation of PLK1 and activating the Aurora A/PLK1 signaling axis. Overexpression of RACK1 causes centrosome amplification, especially in mammary gland epithelial cells, inducing overactivation of PLK1 followed by premature centriole disengagement and centriole re-duplication. Other proteins, including hypoxia-inducible factor α, von Hippel-Lindau protein, heat-shock protein 90, β-catenin, and glycogen synthase kinase-3β, interact with RACK1 and play roles in centrosome regulation. In this review, we focus on the roles and underlying molecular mechanisms of RACK1 in centrosome regulation mediated by its interaction with different proteins and the modulation of their functions.In this study, the effect of the quantity of lipid-based formulations (LBFs) on the oral absorption of ritonavir (RTV), a model for poorly water-soluble drugs, was investigated. Two types of LBFs, comprising short- and medium-chain lipids (LBF-SMC) and long-chain lipids (LBF-LC) loaded with different masses of RTV, were prepared. Then, the respective LBFs were dispersed in distilled water at concentrations of 1.0, 2.0, and 3.0% w/w, which provided the same drug concentration for all formulations. When 1.0% LBF-SMC and LBF-LC were orally administered to rats, the oral absorption was significantly improved compared with that of the suspension (a reference formulation) because of enhanced solubilization of RTV in the gastrointestinal tract; however, this improvement was lower for LBF-LC than for LBF-SMC. The oral absorption decreased with increasing LBF concentration for both LBF-SMC and LBF-LC. The in vitro permeation in sequence with in vitro digestion revealed that this phenomenon was caused by a reduction in the free drug concentration in the gastrointestinal tract. Moreover, the effect of decreasing the free concentration was more remarkable for LBF-LC than for LBF-SMC because of the greater solubilization capacity of LC digestion products. These findings may be useful for designing improved drug delivery systems.The present study aims to determine the major metabolites of amentoflavone (AMF) and further evaluate their inhibitory effects on PARP-1. First, different fractions (Frs. 1-9), which were collected according to retention time of AMF metabolites based on UHPLC-QTOF-MS/MS qualitative analysis, were evaluated on their inhibitory effects against PARP-1. Then, two mono-sulfate metabolites in the fractions with potent PARP-1 inhibitory effect were targetedly semi-synthesized. Moreover, three mono-sulfate conjugates (compound 8, 9 and 10), including one disulfate conjugate (compound 10), were isolated and their structures were fully elucidated by UHPLC-QTOF-MS/MS and NMR. Finally, the binding mode of compound 8 (amentoflavone-4‴-O-sulfate) toward PARP-1 and its potentiation on carboplatin (CBP) in A549 cells were investigated. This study was the first report on bioactivity evaluation of AMF metabolites in rat bile on PARP-1 and the potentiation of compound 8 on carboplatin (CBP) in A549 cells in vitro. This paper also provided scientific basis for the AMF metabolites on PARP-1 inhibition and chemosensitization.Ramsey’s economic theory of saving (RTS) estimates how much of its commodities a nation should save to safeguard the well-being of future generations. Since RTS retains many attractive qualities such as simplicity, strength, breadth and generality, here we ask if it would be useful to investigate biophysical issues. Specifically, we focus on a biological topic that lends itself as a backdrop for the study of the imbalance between intake and expenditure, i.e., the evaluation of the multicellular living organisms’ energetic requirements and constraints. Our problem is to find at each time the optimum distribution and the right balance of the cellular energy budget between consumption and storage how much must a living organism spare to increase its chances of survival over long periods? To give an operational example, we discuss the ATP requirements in the central nervous system during the spontaneous and the evoked activity of the brain, showing that the experimentally detected values of energetic expenditure during neural computations match well with the estimations provided by RTS. Suggesting how to find the optimum allocation of the available energy between expenditure and saving at each time, RTS approaches to biological energy budgets may have a wide range of experimental applications, such as a) optimization of the long-term survival chances of either immortalized cell cultures, or beneficial bacterial colonies and exogenous probiotic mixtures; b) eradication of detrimental biofilms, such as, e.g., heart valves’ Streptococcus colonies; c) novel anti-stress and anti-ageing strategies.

Alumina ceramic-on-ceramic bearings are used in total hip arthroplasty (THA) because of their wear-resistant and inert properties. In this study, we assessed the clinical and radiographic outcomes of patients undergoing primary cementless ceramic-on-ceramic THA at a minimum follow-up of 20 years.

A series of 301 consecutive primary THAs in 283 patients were assessed. Clinically, patients were assessed with the modified Harris Hip Score (HHS) and pain questionnaires. Anteroposterior radiographs of the pelvis and lateral radiographs of the hip were used to radiologically assess the implant. Patients were classified as lost to follow-up if they could not be contacted on multiple occasions or did not wish to participate further in this study.

At twenty years after operation, 60 patients had died of a cause unrelated to surgery, 16 had experienced complications requiring reoperation, and 100 hips had both clinical assessments and radiographs at a minimum of 20 years of follow-up. The average HHS improved from 56.1 (range 17-89) before THA to 92.5 (range 63-100) at the latest follow-up. The classification of the HHS was good or excellent in 96.4% of patients. Only 1.8% of patients still had moderate residual pain at the thigh or groin. Selleckchem TVB-3166 Radiographically, all patients demonstrated bony ingrowth but no clinical symptoms of loosening. The overall survival rate of the implants was 94.2% at 20 years with revision for any reason as the end point.

Long-Term follow-up in our series showed excellent implant survival, excellent functional outcomes, and minimal late complications. There was no significant radiographic evidence of failure at a minimum of 20 years after THA.

Therapeutic Level IV.

Therapeutic Level IV.

Abnormal spinopelvic relationships may place patients at an increased risk for instability after primary total hip arthroplasty. The purpose of this study was to determine if radiographic markers on a standing anteroposterior (AP) pelvis radiograph could identify patients with sagittal spinopelvic imbalance or spinal stiffness.

Patients undergoing primary total hip arthroplasty at a single institution from 2017 to 2020 with standing AP pelvis radiographs and sitting/standing lateral radiographs were identified. AP pelvis radiographs were assessed for the following lumbosacral hardware, spine osteophytes, disc space narrowing, scoliosis>5°, pelvic obliquity>5°, and overlap of the sacrococcygeal junction/pubic symphysis. Patients with spinopelvic imbalance and/or spinopelvic stiffness were identified. Univariate and multivariate analyses were performed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.

Four hundred eighty-six patients were included. Prevalence of isolated sagittal spinopelvic imbalance and isolated spinopelvic stiffness was 12% and 21%, respectively; 11% of patients had sagittal imbalance and stiffness. Overlap of the sacrococcygeal junction/pubic symphysis (OR= 10.2, 95% CI= 5.3-19.8) and presence of lumbosacral hardware (OR= 4.4, 95% CI= 2.0-9.4) were markers of an increased risk of combined sagittal imbalance and stiffness. Seventy-nine percent of patients with overlap of the sacrococcygeal junction and pubic symphysis and 82% of patients with lumbosacral hardware had an abnormal spinopelvic relationship.

Isolated sagittal imbalance and stiffness were difficult to predict on standing AP pelvis radiographs. Overlap of the sacrococcygeal junction/pubic symphysis and presence of lumbosacral hardware associated with a higher risk of combined sagittal imbalance/stiffness and were present in ≥79% of patients with an abnormal spinopelvic relationship.

IV; retrospective cohort study.

IV; retrospective cohort study.

Fixation options for revision total knee arthroplasty (rTKA) have expanded and now include cementless metaphyseal fixation. The utilization rates of these implants in the United States are not well known. The purpose of this study was to analyze trends in cementless metaphyseal fixation for rTKA within the American Joint Replacement Registry (AJRR).

The AJRR was queried for the years 2015-2019 to identify all rTKA with implant data. Trends in the use of cementless sleeves, metaphyseal cones, and any cementless metaphyseal fixation (sleeves+ cones) were examined over the study period using logistic regression analysis.

Twenty thousand two hundred and eighty rTKA were analyzed. Cementless metaphyseal fixation was used in 16% of rTKA and significantly increased over the study period (14% to 19%, P < .0001). Cementless metaphyseal fixation was more frequently utilized during revision for aseptic loosening than other diagnoses (OR 1.014, 95% CI 1.001-1.027). Cementless sleeve utilization decreased over time (11% to 9%, P= .004), driven by decreased use on the femur (4% to 2%, P < .0001). The use of cones increased significantly over time (3% to 9%, P < .0001), driven by increased use on the tibia (2% to 9%, P < .0001). Cones were 22 times more likely to be utilized on the tibia relative to the femur (P < .0001) and were more likely to be used in revisions for infection (OR 1.103, 95% CI 1.089-1.117) and aseptic loosening (OR 1.764, 95% CI 1.728-1.800).

Cementless metaphyseal fixation has grown in popularity yet, still comprised only 16% of rTKA over a 5-year period. Most of the increase was due to the utilization of tibial metaphyseal cones.

Cementless metaphyseal fixation has grown in popularity yet, still comprised only 16% of rTKA over a 5-year period. Most of the increase was due to the utilization of tibial metaphyseal cones.