-
Theranostics 2019Peri-prosthetic osteolysis (PPO) is mainly induced by wear particles and represents the leading cause of implant failure and revision surgery. Previous studies have...
Peri-prosthetic osteolysis (PPO) is mainly induced by wear particles and represents the leading cause of implant failure and revision surgery. Previous studies have identified mitigation of wear particle-induced inflammation and bone resorption as the main approaches to treat PPO. Recently, wear particle-induced reduction of bone formation around the prosthesis was identified as a major factor in the development of PPO. Acetyl-11-keto-β-boswellic acid (AKBA), a derivative of frankincense, has been shown to play a potential role in bone metabolism. However, whether AKBA enhances bone formation in wear particle-induced osteolysis remains unknown. In this study, we examined whether AKBA attenuates titanium particle-induced osteogenic reduction. Titanium particles were used to induce osteolysis in murine calvaria, and micro-CT and histological analyses were used to evaluate the results. Mouse osteoblast cells, MC3T3-E1 were co-cultured with titanium particles to determine their effect on osteoblast formation . We demonstrated that AKBA treatment significantly inhibited titanium particle-induced osteogenic inhibition by enhancing osteogenesis both and . AKBA treatment also enhanced the phosphorylation of GSK-3β, decreased the degradation of β-catenin, and increased the translocation of β-catenin from the cytoplasm to the nucleus. Taken together, these results showed that AKBA treatment attenuated titanium-induced osteogenic inhibition by activating the GSK-3β/β-catenin signaling pathway. These findings suggest that AKBA is a promising new target in the prevention and treatment of PPO.
Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Calcification, Physiologic; Cell Differentiation; Cell Line; Glycogen Synthase Kinase 3 beta; Male; Mice, Inbred C57BL; Osteogenesis; Osteolysis; Pyrimidinones; Signal Transduction; Skull; Titanium; Triterpenes; beta Catenin
PubMed: 31695758
DOI: 10.7150/thno.35988 -
Journal of the American Heart... Mar 2018The cardiovascular effects of low-level environmental radiation exposures are poorly understood. Although particulate matter (PM) has been linked to cardiovascular...
BACKGROUND
The cardiovascular effects of low-level environmental radiation exposures are poorly understood. Although particulate matter (PM) has been linked to cardiovascular morbidity and mortality, and elevated blood pressure (BP), the properties promoting its toxicity remain uncertain. Addressing a knowledge gap, we evaluated whether BP increased with higher exposures to radioactive components of ambient PM, herein referred to as particle radioactivity (PR).
METHODS AND RESULTS
We performed a repeated-measures analysis of 852 men to examine associations between PR exposure and BP using mixed-effects regression models. As a surrogate for PR, we used gross β activity, measured by the US Environmental Protection Agency's radiation monitoring network. Higher PR exposure was associated with increases in both diastolic BP and systolic BP, for exposures from 1 to 28 days. An interquartile range increase in 28-day PR exposure was associated with a 2.95-mm Hg increase in diastolic BP (95% confidence interval, 2.25-3.66; <0.001) and a 3.94-mm Hg increase in systolic BP (95% confidence interval, 2.62-5.27; <0.001). For models including both PR and PM ≤2.5 µm, the PR-BP associations remained stable and significant. For models including PR and black carbon or PR and particle number, the PR-BP associations were attenuated; however, they remained significant for many exposure durations.
CONCLUSIONS
This is the first study to demonstrate the potential adverse effects of PR on both systolic and diastolic BPs. These were independent and similar in magnitude to those of PM ≤2.5 µm, black carbon, and particle number. Understanding the effects of particle-bound radionuclide exposures on BP may have important implications for environmental and public health policy.
Topics: Age Factors; Aged; Aging; Beta Particles; Blood Pressure; Environmental Monitoring; Humans; Longitudinal Studies; Male; Middle Aged; Particulate Matter; Radiation Exposure; Radiation Monitoring; Risk Assessment; Risk Factors; Sex Factors; Time Factors
PubMed: 29545261
DOI: 10.1161/JAHA.117.008245 -
European Journal of Nuclear Medicine... Nov 2019To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and...
PURPOSE
To develop a prostate-specific membrane antigen (PSMA)-targeted radiotherapeutic for metastatic castration-resistant prostate cancer (mCRPC) with optimized efficacy and minimized toxicity employing the β-particle radiation of Lu.
METHODS
We synthesized 14 new PSMA-targeted, Lu-labeled radioligands (Lu-L1-Lu-L14) using different chelating agents and linkers. We evaluated them in vitro using human prostate cancer PSMA(+) PC3 PIP and PSMA(-) PC3 flu cells and in corresponding flank tumor models. Efficacy and toxicity after 8 weeks were evaluated at a single administration of 111 MBq for Lu-L1, Lu-L3, Lu-L5 and Lu-PSMA-617. Efficacy of Lu-L1 was further investigated using different doses, and long-term toxicity was determined in healthy immunocompetent mice.
RESULTS
Radioligands were produced in high radiochemical yield and purity. Cell uptake and internalization indicated specific uptake only in PSMA(+) PC3 cells. Lu-L1, Lu-L3 and Lu-L5 demonstrated comparable uptake to Lu-PSMA-617 and Lu-PSMA-I&T in PSMA-expressing tumors up to 72 h post-injection. Lu-L1, Lu-L3 and Lu-L5 also demonstrated efficient tumor regression at 8 weeks. Lu-L1 enabled the highest survival rate. Necropsy studies of the treated group at 8 weeks revealed subacute damage to lacrimal glands and testes. No radiation nephropathy was observed 1 year post-treatment in healthy mice receiving 111 MBq of Lu-L1, most likely related to the fast renal clearance of this agent.
CONCLUSIONS
Lu-L1 is a viable clinical candidate for radionuclide therapy of PSMA-expressing malignancies because of its high tumor-targeting ability and low off-target radiotoxic effects.
Topics: Animals; Glutamate Carboxypeptidase II; Isotope Labeling; Lutetium; Male; Mice; Molecular Weight; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radiometry; Radiopharmaceuticals
PubMed: 31399803
DOI: 10.1007/s00259-019-04434-0 -
Environment International Mar 2024Sporadic Alzheimer's disease (AD) occurs in 99% of all cases and can be influenced by air pollution such as diesel emissions and more recently, an iron oxide particle,...
BACKGROUND
Sporadic Alzheimer's disease (AD) occurs in 99% of all cases and can be influenced by air pollution such as diesel emissions and more recently, an iron oxide particle, magnetite, detected in the brains of AD patients. However, a mechanistic link between air pollutants and AD development remains elusive.
AIM
To study the development of AD-relevant pathological effects induced by air pollutant particle exposures and their mechanistic links, in wild-type and AD-predisposed models.
METHODS
C57BL/6 (n = 37) and APP/PS1 transgenic (n = 38) mice (age 13 weeks) were exposed to model pollutant iron-based particle (Fe-FeO, d = 493 ± 133 nm), hydrocarbon-based diesel combustion particle (43 ± 9 nm) and magnetite (FeO, 153 ± 43 nm) particles (66 µg/20 µL/third day) for 4 months, and were assessed for behavioural changes, neuronal cell loss, amyloid-beta (Aβ) plaque, immune response and oxidative stress-biomarkers. Neuroblastoma SHSY5Y (differentiated) cells were exposed to the particles (100 μg/ml) for 24 h, with assessments on immune response biomarkers and reactive oxygen species generation.
RESULTS
Pollutant particle-exposure led to increased anxiety and stress levels in wild-type mice and short-term memory impairment in AD-prone mice. Neuronal cell loss was shown in the hippocampal and somatosensory cortex, with increased detection of Aβ plaque, the latter only in the AD-predisposed mice, with the wild-type not genetically disposed to form the plaque. The particle exposures however, increased AD-relevant immune system responses, including inflammation, in both strains of mice. Exposures also stimulated oxidative stress, although only observed in wild-type mice. The in vitro studies complemented the immune response and oxidative stress observations.
CONCLUSIONS
This study provides insights into the mechanistic links between inflammation and oxidative stress to pollutant particle-induced AD pathologies, with magnetite apparently inducing the most pathological effects. No exacerbation of the effects was observed in the AD-predisposed model when compared to the wild-type, indicating a particle-induced neurodegeneration that is independent of disease state.
Topics: Humans; Mice; Animals; Infant; Alzheimer Disease; Air Pollutants; Ferrosoferric Oxide; Mice, Inbred C57BL; Amyloid beta-Peptides; Inflammation; Plaque, Amyloid; Biomarkers; Disease Models, Animal
PubMed: 38412566
DOI: 10.1016/j.envint.2024.108512 -
Journal of Nuclear Medicine : Official... Jul 2018The use of radioactive sources to deliver cytotoxic ionizing radiation to disease sites dates back to the early 20th century, with the discovery of radium and its... (Review)
Review
The use of radioactive sources to deliver cytotoxic ionizing radiation to disease sites dates back to the early 20th century, with the discovery of radium and its physiologic effects. α-emitters are of particular interest in the field of clinical oncology for radiotherapy applications. The first part of this review explored the basic radiochemistry, high cell-killing potency, and availability of α-emitting radionuclides, together with hurdles such as radiolabeling methods and daughter redistribution. The second part of this review will give an overview of the most promising and current uses of α-emitters in preclinical and clinical studies.
Topics: Alpha Particles; Animals; Beta Particles; Humans; Radiochemistry; Translational Research, Biomedical
PubMed: 29496984
DOI: 10.2967/jnumed.117.204651 -
Food & Function Apr 2021In this study, β-carotene loaded oil-in-water emulsions were stabilized by complex interfaces composed of propylene glycol alginate (PGA), rhamnolipids (Rha), and zein...
In this study, β-carotene loaded oil-in-water emulsions were stabilized by complex interfaces composed of propylene glycol alginate (PGA), rhamnolipids (Rha), and zein colloidal particles (ZCPs). The influence of mixed biopolymer-surfactant, biopolymer-particle, surfactant-particle and biopolymer-surfactant-particle interfaces on the performance of the emulsions was investigated. The stability, microstructure, rheological properties, and in vitro gastrointestinal digestion of the emulsions were controlled by regulating the adding sequence and mass ratio of the multiple stabilizers. The droplet size of the emulsion was in the range of 14-77 μm. After encapsulation into the emulsions stabilized by the complex interfaces, the photothermal stability of β-carotene were increased by 41.53% and 21.52%, respectively. The co-existence of particles, biopolymers, and surfactants could induce competitive displacement, multilayer deposition and an interparticle network at the interface. Compared with a single PGA- or Rha-stabilized emulsion, the complex interface-stabilized emulsion reduced the release of FFA by 28.06% and 26.16%, respectively. The interfacial composition of the emulsion and the delayed lipid digestion further affected the bioaccessibility of β-carotene in the gastrointestinal tract (GIT). The mixed biopolymer-particle-surfactant interface-stabilized emulsion could be incorporated in foods, pharmaceuticals and cosmetics for excellent stability, targeted nutrient delivery and controlled lipolysis.
Topics: Biological Availability; Biopolymers; Digestion; Drug Stability; Elasticity; Emulsions; Gastrointestinal Tract; Microscopy, Electron, Scanning; Particle Size; Pepsin A; Surface-Active Agents; Viscosity; Zein; beta Carotene
PubMed: 33877248
DOI: 10.1039/d0fo02975k -
Polymers Jun 2022The steady state of motion of two particles in Poiseuille flow of power-law fluid is numerically studied using the lattice Boltzmann method in the range of Reynolds...
The steady state of motion of two particles in Poiseuille flow of power-law fluid is numerically studied using the lattice Boltzmann method in the range of Reynolds number 20 ≤ ≤ 60, diameter ratio of two particles 0.125 ≤ ≤ 2.4, and power-law index of the fluid 0.4 ≤ ≤ 1.2. Some results are validated by comparing with other available results. The effects of , and on the steady state of motion of two particles are discussed. The results show that, for two particles of the same diameter, the particle spacing in the steady state is independent of . In shear-thinning fluid, increases rapidly at first and then slowly, finally approaching a constant for different . In shear-thickening fluid, although tends to be stable in the end, the values of after stabilization are different. For two particles of different sizes, does not always reach a stable state, and whether it reaches a stable state depends on . When the small particle is downstream, increases rapidly at first and then slowly in shear-thickening fluid, but increases rapidly at first and then decreases slowly, finally approaching a constant in a shear-thinning fluid. In shear-thinning fluid, the larger is, the smaller is. In shear-thickening fluid, has no effect on in steady-state. When the large particle is downstream, increases rapidly at first and then slowly in shear-thinning fluid but increases rapidly at first and then decreases in a shear-thickening fluid. The effect of on in the steady state is obvious. In shear-thinning fluid, increases rapidly at first and then slowly, the larger is, the smaller is. In shear- thickening fluid, will reach a stable state.
PubMed: 35745944
DOI: 10.3390/polym14122368 -
American Journal of Cancer Research 2019Pertuzumab is clinically employed in the treatment of cancers over-expressing human epidermal growth factor receptor 2 (HER2). Herein, we developed dual-labeled...
Pertuzumab is clinically employed in the treatment of cancers over-expressing human epidermal growth factor receptor 2 (HER2). Herein, we developed dual-labeled pertuzumab with a radionuclide (Zr) and a near-infrared fluorophore (IRDye 800CW) to investigate the feasibility of utilizing dual-labeled monoclonal antibodies (mAbs) with numerous imaging modalities for preoperative imaging and image-guided surgery in ovarian cancer models. MAbs were dually-labeled with Zr and IRDye 800CW to generate Zr-Df-pertuzumab-800CW or Zr-Df-IgG-800CW. Serial positron emission tomography (PET) and near-infrared fluorescence (NIRF) images were acquired up to 72 hours after injection of dual-labeled mAbs to map the tracers' biodistributions. After the last time point, image-guided tumor resection was executed using different modalities (NIRF, Cerenkov luminescence [CL], and β particle imaging) and studies including biodistribution assays and histology analysis were performed to confirm the imaging data. SKOV3 ovarian cancer cells showed high expression of HER2 and pertuzumab conjugated with Df and IRDye 800CW maintained its binding affinity for these cells. For PET imaging in subcutaneous xenograft ovarian cancer models, Zr-Df-pertuzumab-800CW showed a significantly higher tumor-to-muscle ratio compared to the nonspecific Zr-Df-IgG-800CW from 24 hours after injection through the last time point (72 h: 30.7 ± 7.4 vs. 7.5 ± 1.8, < 0.01, = 3-4). During image-guided surgery, three imaging modalities including NIRF, CL, and β particle imaging could detect ovarian cancer in both subcutaneous and orthotopic models and each exhibited its own imaging characteristics. In addition, imaging and biodistribution studies as well as histology analysis corroborated the imaging results. Therefore, we concluded that this single radiolabeled tracer can provide all-in-one contrast for multiple imaging modalities. The dual-labeled mAbs may hold promise to be employed for image-guided tumor surgery as well as diagnosis and staging through balancing out the strengths and weaknesses of various modalities such as PET/CT, NIRF, CL, and β particle imaging.
PubMed: 31392081
DOI: No ID Found -
Journal of Structural Biology Nov 2018Particle picking is a crucial first step in the computational pipeline of single-particle cryo-electron microscopy (cryo-EM). Selecting particles from the micrographs is...
Particle picking is a crucial first step in the computational pipeline of single-particle cryo-electron microscopy (cryo-EM). Selecting particles from the micrographs is difficult especially for small particles with low contrast. As high-resolution reconstruction typically requires hundreds of thousands of particles, manually picking that many particles is often too time-consuming. While template-based particle picking is currently a popular approach, it may suffer from introducing manual bias into the selection process. In addition, this approach is still somewhat time-consuming. This paper presents the APPLE (Automatic Particle Picking with Low user Effort) picker, a simple and novel approach for fast, accurate, and template-free particle picking. This approach is evaluated on publicly available datasets containing micrographs of β-galactosidase, T20S proteasome, 70S ribosome and keyhole limpet hemocyanin projections.
Topics: Algorithms; Cryoelectron Microscopy; Imaging, Three-Dimensional; Pattern Recognition, Automated; beta-Galactosidase
PubMed: 30134153
DOI: 10.1016/j.jsb.2018.08.012 -
International Journal of Molecular... Jun 2023Periprosthetic osteolysis (PPO) induced by wear particles is the most severe complication of total joint replacement; however, the mechanism behind PPO remains elusive....
Periprosthetic osteolysis (PPO) induced by wear particles is the most severe complication of total joint replacement; however, the mechanism behind PPO remains elusive. Previous studies have shown that osteocytes play important roles in wear-particle-induced osteolysis. In this study, we investigated the effects of connexin 43 (Cx43) on the regulation of osteocyte-to-osteoblast differentiation. We established an in vivo murine model of calvarial osteolysis induced by titanium (Ti) particles. The osteolysis characteristic and osteogenesis markers in the and were observed. The calvarial osteolysis induced by Ti particles was partially attenuated in . The expression of β-catenin and osteogenesis markers increased significantly in . In vitro, the osteocytic cell line MLO-Y4 was treated with Ti particles. The co-culturing of MLO-Y4 cells with MC3T3-E1 osteoblastic cells was used to observe the effects of Ti-treated osteocytes on osteoblast differentiation. When Cx43 of MLO-Y4 cells was silenced or overexpressed, β-catenin was detected. Additionally, co-immunoprecipitation detection of Cx43 and β-catenin binding in MLO-Y4 cells and MC3T3-E1 cells was performed. Finally, β-catenin expression in MC3T3-E1 cells and osteoblast differentiation were evaluated after 18α-glycyrrhetinic acid (18α-GA) was used to block the intercellular communication of Cx43 between MLO-Y4 and MC3T3-E1 cells. Ti particles increased Cx43 expression and decreased β-catenin expression in MLO-Y4 cells. The silencing of Cx43 increased the β-catenin expression, and the over-expression of Cx43 decreased the β-catenin expression. In the co-culture model, Ti treatment of MLO-Y4 cells inhibited the osteoblastic differentiation of MC3T3-E1 cells and Cx43 silencing in MLO-Y4 cells attenuated the inhibitory effects on osteoblastic differentiation. With Cx43 silencing in the MLO-Y4 cells, the MC3T3-E1 cells, co-cultured alongside MLO-Y4, displayed decreased Cx43 expression, increased β-catenin expression, activation of Runx2, and promotion of osteoblastic differentiation in vitro co-culture. Finally, Cx43 expression was found to be negatively correlated to the activity of the Wnt signaling pathway, mostly through the Cx43 binding of β-catenin from its translocation to the nucleus. The results of our study suggest that Ti particles increased Cx43 expression in osteocytes and that osteocytes may participate in the regulation of osteoblast function via the Cx43 during PPO.
Topics: Mice; Animals; Osteocytes; beta Catenin; Connexin 43; Titanium; Osteolysis; Cell Differentiation; Osteoblasts
PubMed: 37446062
DOI: 10.3390/ijms241310864