Search

BACKGROUND: Radiation induces rapid bone loss and enhances bone resorption and adipogenesis, leading to an increased risk of bone fracture. There is still a lack of effective preventive or therapeutic method for irradiation-induced bone injury. Receptor activator of nuclear factor κB ligand (RANKL) provides the crucial signal to induce osteoclast differentiation and plays an important role in bone resorption. However, the mechanisms of radiation-induced osteoporosis are not fully understood. AIM: To investigate the role of CR6-interacting factor-1 (Crif1) in osteoclastogenesis after radiation and its possible mechanism. METHODS: C57BL/6 mice were exposed to Co-60 gamma rays and received 5 Gy of whole-body sublethal irradiation at a rate of 0.69 Gy/min. For in vitro study, mouse bone marrow mesenchymal stem/stromal cells (BM-MSCs) were irradiated with Co-60 at a single dose of 9 Gy. For osteoclast induction, monocyte-macrophage RAW264.7 cells were cocultured with mouse BM-MSCs for 7 d. ClusPro and InterProSurf were used to investigate the interaction interface in Crif1 and protein kinase cyclic adenosine monophosphate (cAMP)-activited catalytic subunit alpha complex. Virtual screening using 462608 compounds from the Life Chemicals database around His120 of Crif1 was carried out using the program Autodock_vina. A tetrazolium salt (WST-8) assay was carried out to study the toxicity of compounds to different cells, including human BM-MSCs, mouse BM-MSCs, and Vero cells. RESULTS: Crif1 expression increased in bone marrow cells after radiation in mice. Overexpression of Crif1 in mouse BM-MSCs and radiation exposure could increase RANKL secretion and promote osteoclastogenesis in vitro. Deletion of Crif1 in BM-MSCs could reduce both adipogenesis and RANKL expression, resulting in the inhibition of osteoclastogenesis. Deletion of Crif1 in RAW264.7 cells did not affect the receptor activator of nuclear factor κB expression or osteoclast differentiation. Following treatment with protein kinase A (PKA) agonist (forskolin) and inhibitor (H-89) in mouse BM-MSCs, Crif1 induced RANKL secretion via the cAMP/PKA pathway. Moreover, we identified the Crif1-protein kinase cyclic adenosine monophosphate-activited catalytic subunit alpha interaction interface by in silico studies and shortlisted interface inhibitors through virtual screening on Crif1. Five compounds dramatically suppressed RANKL secretion and adipogenesis by inhibiting the cAMP/PKA pathway. CONCLUSION: Crif1 promotes RANKL expression via the cAMP/PKA pathway, which induces osteoclastogenesis by binding to receptor activator of nuclear factor κB on monocytes-macrophages in the mouse model. These results suggest a role for Crif1 in modulating osteoclastogenesis and provide insights into potential therapeutic strategies targeting the balance between osteogenesis and adipogenesis for radiation-induced bone injury.

Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (ABCG2), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC50 values less than 5 μM using 3H-cholecystokinin octapeptide (3H-CCK8). These BCRP inhibitors belonged to three functional categories of excipients: dyes, surfactants, and flavoring agents. Compared with noninhibitors, BCRP inhibitors had significantly higher molecular weights and SLogP values. The inhibitory effects of excipients identified in membrane vesicles were also evaluated in BCRP-overexpressing HEK293 cells at similar concentrations. Only 1 of the 26 inhibitors of BCRP identified in vesicles inhibited BCRP-mediated 3H-oxypurinol uptake by more than 50%, consistent with the notion that BCRP inhibition depends on transmembrane or intracellular availability of the inhibitors. Collectively, the results of this study provide new information on excipient selection during the development of drug products with active pharmaceutical ingredients that are BCRP substrates.

BackgroundGlucagon-like peptide-1 (GLP-1) has been reported to have beneficial impacts on improving human's metabolism and ameliorating insulin resistance. While insulin is another important and conventional drug in diabetes treatment, but it has an adverse effect on weight gain.PurposeTo make sure whether GLP-1 and insulin play different roles in human adipose-derived stem cells (hADSCs).MethodsWe examined the in vitro roles and molecular mechanisms of liraglutide, a GLP-1 analogue, and human insulin on hADSCs isolated from subcutaneous adipose tissue. Different concentrations (0, 0.1, 1, 10, 100nM) of liraglutide and insulin were added to proliferation and differentiation medium of hADSCs, respectively.ResultsLiraglutide inhibits while insulin promotes the proliferation and differentiation at the concentration of 100nM. Moreover, the levels of GSK-3 increase during differentiation and liraglutide could down-regulate it when compared with insulin. We also find that the activation of phosphorylated GSK-3α and GSK-3β is involved in the differentiation roles. And classical and non-classical Wnt pathways all play roles in the differentiation, which are characterized with the up/down-regulation of the expression of adipogenesis genes such as PPAR-γ and CEBP-α.ConclusionLiraglutide and insulin have contrary effects on the proliferation and adipogenesis via Wnt pathway in primary cultured ADSCs. Those effects could partly explain the different roles of GLP-1 and insulin on weight gain and insulin resistance.

Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value

AbstractThis paper provides an overview of the unique modeling and simulation challenges and needs in the system and safety analysis of two common types of High Temperature Gas-cooled Reactor (HTGR) designs. The challenges are associated with the complex core geometry configurations and the change of the dominant heat removal mechanisms between normal operating conditions and decay heat removal transients. This requires that simulation tools utilize models with reasonable length scales and capture both the localized heat transfer and the core-scale heat transfer at the same time. To meet such analysis needs, different methodologies were developed. This includes adopting existing methods and further developing/improving them, as well as proposing innovative methods that leverage advanced computational frameworks such as the Multiphysics Object Oriented Simulation Environment (MOOSE). [ABSTRACT FROM AUTHOR]

This study aimed to comprehensively characterize the gut microbiota in diarrheal mink. We conducted Shotgun metagenomic sequencing on samples from five groups of diarrheal mink and five groups of healthy mink. The microbiota α-diversity and Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology did not show significant differences between the groups. However, significant differences were observed in microbiota β-diversity and the function of carbohydrate-active enzymes (CAZymes) between diarrheal and healthy mink. Specifically, The relative abundance of Firmicutes was lower, whereas that of Bacteroidetes was higher in diarrheal mink. Fusobacteria were enriched as invasive bacteria in the gut of diarrheal mink compared with healthy mink. In addition, Escherichia albertii was identified as a new bacterium in diarrheal mink. Regarding functions, nicotinate and nicotinamide metabolism and glycoside hydrolases 2 (GH2) family were the enhanced KEGG orthology and CAZymes in diarrheal mink. Furthermore, the diversity and number of antibiotic-resistant genes were significantly higher in the diarrheal mink group than in the healthy group. These findings enhance our understanding of the gut microbiota of adult mink and may lead to new approaches to the diagnosis and treatment of mink diarrhea. [ABSTRACT FROM AUTHOR]

AbstractThe System Analysis Module (SAM), developed at Argonne National Laboratory and by collaborators at other organizations, is for advanced non–light water reactor safety analysis. SAM aims to provide fast-running, modest-fidelity, whole-plant transient analysis capabilities that are essential for fast-turnaround design scoping and engineering analyses of advanced reactor concepts. To facilitate code development, SAM utilizes the MOOSE object-oriented application framework, its underlying finite element library, and linear and nonlinear solvers to leverage modern advanced software environments and numerical methods. SAM aims to solve tightly coupled physical phenomena, including fission reaction, heat transfer, fluid dynamics, and thermal-mechanical responses in advanced reactor structures, systems, and components with high accuracy and efficiency.This paper gives an overview of the SAM code development, including goals and functional requirements, physical models, current capabilities, verification and validation, software quality assurance, and examples of simulations for advanced nuclear reactor applications. [ABSTRACT FROM AUTHOR]

Temperature fluctuations induced by mountain waves can play a crucial role in the formation of polar stratospheric clouds (PSCs). In particular, the cold phase of the waves can lower local temperatures sufficiently to trigger PSC formation, even when large-scale background temperatures are too high. To provide new quantitative constraints on the relevance of this effect, this study analyzes a decade (2002–2012) of ice PSC detections obtained from Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) measurements and ERA5 data in the polar winter lower stratosphere. In the MIPAS observations, we find that approximately 52 % of the Arctic ice PSCs and 26 % of the Antarctic ice PSCs are detected at temperatures above the local Tice. Ice PSCs above Tice are concentrated around mountainous regions and their downwind directions. A backward-trajectory analysis is performed to investigate the temperature history of each ice PSC observation. The cumulative fraction of ice PSCs above Tice increases as the trajectory gets closer to the observation point. The most significant change in the fraction of ice PSCs above Tice occurs within the 6 h preceding the observations. At the observation point, the mean fractions of ice PSCs above Tice , taking into account temperature fluctuations along the backward trajectory, are 33 % in the Arctic and 9 % in the Antarctic. The results provide a quantitative assessment of the occurrence of ice PSCs above Tice in connection with orographic waves. Additionally, the observational statistics presented can be utilized for comparison with chemistry climate simulations. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a highly prevalent progressive joint disease that still requires an optimal therapeutic approach. Intermittent fasting is an attractive dieting strategy for improving health. Here this study shows that intermittent fasting potently relieves medial meniscus (DMM)‐ or natural aging‐induced osteoarthritic phenotypes. Osteocytes, the most abundant bone cells, secrete excess neuropeptide Y (NPY) during osteoarthritis, and this alteration can be altered by intermittent fasting. Both NPY and the NPY‐abundant culture medium of osteocytes (OCY‐CM) from osteoarthritic mice possess pro‐inflammatory, pro‐osteoclastic, and pro‐neurite outgrowth effects, while OCY‐CM from the intermittent fasting‐treated osteoarthritic mice fails to induce significant stimulatory effects on inflammation, osteoclast formation, and neurite outgrowth. Depletion of osteocyte NPY significantly attenuates DMM‐induced osteoarthritis and abolishes the benefits of intermittent fasting on osteoarthritis. This study suggests that osteocyte NPY is a key contributing factor in the pathogenesis of osteoarthritis and intermittent fasting represents a promising nonpharmacological antiosteoarthritis method by targeting osteocyte NPY. [ABSTRACT FROM AUTHOR]

AbstractThis work presents the development and implementation of the one-dimensional freezing model in system analysis code SAM (System Analysis Module), code verification using analytical solutions, and code demonstration of a postulated overcooling transient for a fluoride salt–cooled high-temperature reactor (FHR) system and safety analysis applications. This paper first summarizes the freezing model, finite element numerical method, and special numerical treatment for handling transitions between single- and two-phase conditions. Analytical solutions are derived for two cases, with and without solid walls, for code verification purposes. As expected, the numerical results predicted by SAM agree very well with the analytical solution. A code demonstration is then performed on a postulated protected overcooling transient event of a generic reference pebble bed FHR design. The code was found to successfully predict salt freezing during such a postulated event. However, due to the lack of salt freezing testing data, code validation is not performed in this work, but will be pursued in future studies when such data become available. [ABSTRACT FROM AUTHOR]

Chronic inflammation at diabetic wound sites results in the uncontrolled accumulation of pro‐inflammatory factors and reactive oxygen species (ROS), which impedes cell proliferation and delays wound healing. To promote the healing of diabetic wounds, chitosan/gelatin hydrogels containing ceria nanoparticles (CNPs) of various sizes were created in the current study. CNPs' efficacy in removing O2•−, •OH, and H2O2 was demonstrated, and the scavenging ability of CNPs of varying sizes was compared. The in vitro experiments demonstrated that hydrogels containing CNPs could effectively protect cells from ROS‐induced damage and facilitate mouse fibroblast migration. Furthermore, during the treatment of diabetic wounds in vivo, hydrogels containing CNPs exhibited anti‐inflammatory activity and could reduce the expression of the pro‐inflammatory factors TNF‐α (above 30%), IL‐6 (above 90%), and IL‐1β (above 80%), and effectively promote wound closure (above 80%) by inducing re‐epithelialization, collagen deposition, and angiogenesis. In addition, the biological properties and therapeutic effects of hydrogels containing CNPs of various sizes were compared and discussed. The finding revealed that hydrogels with 4 nm CNPs exhibited more significant biological properties and had implications for diabetic wound treatment. [ABSTRACT FROM AUTHOR]

Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (ANPs), with organic anion transporter 1 [(OAT1) SLC22A6] and identified a key amino acid residue responsible for these differences. In OAT1 stably transfected human embryonic kidney 293 cells, the Km value of tenofovir for human OAT1 (hOAT1) was significantly lower than for OAT1 orthologs from common preclinical animals, including cynomolgus monkey, mouse, rat, and dog. Chimeric and site-directed mutagenesis studies along with comparative structure modeling identified serine at position 203 (S203) in hOAT1 as a determinant of its lower Km value. Furthermore, S203 is conserved in apes, and in contrast alanine at the equivalent position is conserved in preclinical animals and Old World monkeys, the most related primates to apes. Intriguingly, transport efficiencies are significantly higher for OAT1 orthologs from apes with high serum uric acid (SUA) levels than for the orthologs from species with low serum uric acid levels. In conclusion, our data provide a molecular mechanism underlying species differences in renal accumulation of nephrotoxic ANPs and a novel insight into OAT1 transport function in primate evolution.

A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease and diabetes. Analysis of data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms in the organic cation transporter, OCT1 (SLC22A1), are significantly associated with higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and an increased risk for type 2 diabetes mellitus, yet the mechanism linking OCT1 to these metabolic traits remains puzzling. Here, we show that OCT1, widely characterized as a drug transporter, plays a key role in modulating hepatic glucose and lipid metabolism, potentially by mediating thiamine (vitamin B1) uptake and hence its levels in the liver. Deletion of Oct1 in mice resulted in reduced activity of thiamine-dependent enzymes, including pyruvate dehydrogenase (PDH), which disrupted the hepatic glucose-fatty acid cycle and shifted the source of energy production from glucose to fatty acids, leading to a reduction in glucose utilization, increased gluconeogenesis, and altered lipid metabolism. In turn, these effects resulted in increased total body adiposity and systemic levels of glucose and lipids. Importantly, wild-type mice on thiamine deficient diets (TDs) exhibited impaired glucose metabolism that phenocopied Oct1 deficient mice. Collectively, our study reveals a critical role of hepatic thiamine deficiency through OCT1 deficiency in promoting the metabolic inflexibility that leads to the pathogenesis of cardiometabolic disease.