28 research outputs found
The effect of quercetin on the antioxidant response and phenotypic development of osteoblasts
Oxidative stress plays a major role in development of osteoporosis, in part, by suppressing the differentiation and function of bone forming osteoblasts. This finding suggests that strategies to prevent or reverse osteoporosis may lie in targeting the osteoblast antioxidant response. Quercetin is an antioxidant flavonoid found abundantly in the diet and in supplements, and is known to induce expression of antioxidant response genes and proteins in a variety of cell types. The purpose of these studies was to examine the extent that quercetin metabolites up-regulate the antioxidant response, to identify cell signaling pathways that might be involved, and to examine the extent that quercetin preserves development of the osteoblast phenotype when cells are cultured in an oxidative stress environment. We hypothesized that quercetin metabolites would up-regulate the antioxidant response, and that this up-regulation would protect cells from oxidative stress-induced suppression. Studies were performed in osteoblast-like cultures isolated from fetal rat calvaria that were treated with 0 to 20 ”M quercetin aglycone (QRC), isorhamnetin (ISO), quercetin-3-O-glucuronide (Q3G) or a 2:1:1 mixture of all three metabolites (10 ”M Q3G: 5 ”M QRC: 5 ”M ISO). The antioxidant response was assessed by measuring expression of antioxidant genes and proteins. Results indicated that QRC and ISO robustly up-regulated expression of two antioxidant response genes and proteins, heme oxygenase-1 (HO-1) and the catalytic subunit of gamma-glutamate cysteine ligase, but Q3G had no effect. Cell signaling protein, ERK1/2, and transcription factor NFkappaB proteins were also down-regulated by quercetin. To examine the effect of quercetin on oxidative stress-induced suppression of osteoblast phenotype, cells were pretreated 12h with 20 ”M QRC followed by incubation with 0 or 300 ”M hydrogen peroxide, a known inducer of oxidative stress. Differentiation was assessed by alkaline phosphatase staining and expression of osteoblast phenotypic gene markers. Pretreating cells with 20 ”M QRC partially blocked hydrogen peroxide-induced suppression of osteoblast phenotype, as indicated by higher levels of alkaline phosphatase staining and gene expression of osteoblast phenotype markers compared to cells pretreated with 0 ”M QRC. QRC also partially blocked hydrogen peroxide-induced up-regulation of HO-1. These results suggest that quercetin produces a low grade antioxidant response that "primes" cells to withstand a subsequent oxidative stress event, which protects development of osteoblast phenotype. These findings offer important insight into the osteoblast antioxidant stress response, and support a link between osteoblast stress signaling and phenotypic development
Zoledronate treatment duration is linked to bisphosphonateârelated osteonecrosis of the jaw prevalence in rice rats with generalized periodontitis
ObjectivesTo determine the extent that zoledronate (ZOL) dose and duration is associated with bisphosphonateârelated osteonecrosis of the jaw (BRONJ) prevalence in rice rats with generalized periodontitis (PD), characterize structural and tissueâlevel features of BRONJâlike lesions in this model, and examine the specific antiâresorptive role of ZOL in BRONJ.Materials and MethodsRice rats (n = 228) consumed high sucroseâcasein diet to enhance generalized PD. Groups of rats received 0, 8, 20, 50 or 125 ”g/kg IV ZOL/4 weeks encompassing osteoporosis and oncology ZOL doses. Rats from each dose group (n = 9â16) were necropsied after 12, 18, 24 and 30 weeks of treatment. BRONJâlike lesion prevalence and tissueâlevel features were assessed grossly, histopathologically and by MicroCT. ZOL bone turnover effects were assessed by femoral peripheral quantitative computed tomography, serum bone turnover marker ELISAs and osteoclast immunolabelling.ResultsPrevalence of BRONJâlike lesions was significantly associated with (a) ZOL treatment duration, but plateaued at the lowest oncologic dose, and (b) there was a similar doseârelated plateau in the systemic antiâresorptive effect of ZOL. ZOL and BRONJâlike lesions also altered the structural and tissueâlevel features of the jaw.ConclusionThe relationship between BRONJâlike lesion prevalence and ZOL dose and duration varies depending on the coâ or preâexisting oral risk factor. At clinically relevant doses of ZOL, BRONJâlike lesions are associated with antiâresorptive activity.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149302/1/odi13052.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149302/2/odi13052_am.pd
Algebraic Distribution of Segmental Duplication Lengths in Whole-Genome Sequence Self-Alignments
Distributions of duplicated sequences from genome self-alignment are characterized, including forward and backward alignments in bacteria and eukaryotes. A Markovian process without auto-correlation should generate an exponential distribution expected from local effects of point mutation and selection on localised function; however, the observed distributions show substantial deviation from exponential form â they are roughly algebraic instead â suggesting a novel kind of long-distance correlation that must be non-local in origin
TNFAIP3 Maintains Intestinal Barrier Function and Supports Epithelial Cell Tight Junctions
Tight junctions between intestinal epithelial cells mediate the permeability of the intestinal barrier, and loss of intestinal barrier function mediated by TNF signaling is associated with the inflammatory pathophysiology observed in Crohn's disease and celiac disease. Thus, factors that modulate intestinal epithelial cell response to TNF may be critical for the maintenance of barrier function. TNF alpha-induced protein 3 (TNFAIP3) is a cytosolic protein that acts in a negative feedback loop to regulate cell signaling induced by Toll-like receptor ligands and TNF, suggesting that TNFAIP3 may play a role in regulating the intestinal barrier. To investigate the specific role of TNFAIP3 in intestinal barrier function we assessed barrier permeability in TNFAIP3â/â mice and LPS-treated villin-TNFAIP3 transgenic mice. TNFAIP3â/â mice had greater intestinal permeability compared to wild-type littermates, while villin-TNFAIP3 transgenic mice were protected from increases in permeability seen within LPS-treated wild-type littermates, indicating that barrier permeability is controlled by TNFAIP3. In cultured human intestinal epithelial cell lines, TNFAIP3 expression regulated both TNF-induced and myosin light chain kinase-regulated tight junction dynamics but did not affect myosin light chain kinase activity. Immunohistochemistry of mouse intestine revealed that TNFAIP3 expression inhibits LPS-induced loss of the tight junction protein occludin from the apical border of the intestinal epithelium. We also found that TNFAIP3 deubiquitinates polyubiquitinated occludin. These in vivo and in vitro studies support the role of TNFAIP3 in promoting intestinal epithelial barrier integrity and demonstrate its novel ability to maintain intestinal homeostasis through tight junction protein regulation
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iEEG-BIDS, extending the Brain Imaging Data Structure specification to human intracranial electrophysiology
The Brain Imaging Data Structure (BIDS) is a community-driven specification for organizing neuroscience data and metadata with the aim to make datasets more transparent, reusable, and reproducible. Intracranial electroencephalography (iEEG) data offer a unique combination of high spatial and temporal resolution measurements of the living human brain. To improve internal (re)use and external sharing of these unique data, we present a specification for storing and sharing iEEG data: iEEG-BIDS
Gaining the Patient Reported Outcomes Measurement Information System (PROMIS) perspective in chronic kidney disease: a Midwest Pediatric Nephrology Consortium study
Chronic kidney disease is a persistent chronic health condition commonly seen in pediatric nephrology programs. Our study aims to evaluate the sensitivity of the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric instrument to indicators of disease severity and activity in pediatric chronic kidney disease
Individual- and neighborhood-level education influences the effect of obesity on prostate cancer treatment failure after prostatectomy
Signatures of Insecticide Selection in the Genome of Drosophila melanogaster
Resistance to insecticides has evolved in multiple insect species, leading to increased application rates and even control failures. Understanding the genetic basis of insecticide resistance is fundamental for mitigating its impact on crop production and disease control. We performed a GWAS approach with the Drosophila Genetic Reference Panel (DGRP) to identify the mutations involved in resistance to two widely used classes of insecticides: organophosphates (OPs, parathion) and pyrethroids (deltamethrin). Most variation in parathion resistance was associated with mutations in the target gene Ace, while most variation in deltamethrin resistance was associated with mutations in Cyp6a23, a gene encoding a detoxification enzyme never previously associated with resistance. A ânested GWASâ further revealed the contribution of other loci: Dscam1 and trpl were implicated in resistance to parathion, but only in lines lacking Wolbachia. Cyp6a17, the paralogous gene of Cyp6a23, and CG7627, an ATP-binding cassette transporter, were implicated in deltamethrin resistance. We observed signatures of recent selective sweeps at all of these resistance loci and confirmed that the soft sweep at Ace is indeed driven by the identified resistance mutations. Analysis of allele frequencies in additional population samples revealed that most resistance mutations are segregating across the globe, but that frequencies can vary substantially among populations. Altogether, our data reveal that the widely used OP and pyrethroid insecticides imposed a strong selection pressure on natural insect populations. However, it remains unclear why, in Drosophila, resistance evolved due to changes in the target site for OPs, but due to a detoxification enzyme for pyrethroids
Functional Analysis of a Unique Troponin C Mutation, GLY159ASP, that Causes Familial Dilated Cardiomyopathy, Studied in Explanted Heart Muscle
Role of Polymer Architecture on the Activity of PolymerâProtein Conjugates for the Treatment of Accelerated Bone Loss Disorders
Polymers
of similar molecular weights and chemical constitution
but varying in their macromolecular architectures were conjugated
to osteoprotegerin (OPG) to determine the effect of polymer topology
on protein activity in vitro and in vivo. OPG is a protein that inhibits
bone resorption by preventing the formation of mature osteoclasts
from the osteoclast precursor cell. Accelerated bone loss disorders,
such as osteoporosis, rheumatoid arthritis, and metastatic bone disease,
occur as a result of increased osteoclastogenesis, leading to the
severe weakening of the bone. OPG has shown promise as a treatment
in bone disorders; however, it is rapidly cleared from circulation
through rapid liver uptake, and frequent, high doses of the protein
are necessary to achieve a therapeutic benefit. We aimed to improve
the effectiveness of OPG by creating OPGâpolymer bioconjugates, employing reversible additionâfragmentation chain transfer
polymerization to create well-defined polymers with branching densities
varying from linear, loosely branched to densely branched. Polymers
with each of these architectures were conjugated to OPG using a âgrafting-toâ
approach, and the bioconjugates were characterized by sodium dodecyl
sulfate polyacrylamide gel electrophoresis. The OPGâpolymer
bioconjugates showed retention of activity in vitro against osteoclasts,
and each bioconjugate was shown to be nontoxic. Preliminary in vivo
studies further supported the nontoxic characteristics of the bioconjugates,
and measurement of the bone mineral density in rats 7 days post-treatment
via peripheral quantitative computed tomography suggested a slight
increase in bone mineral density after administration of the loosely
branched OPGâpolymer bioconjugate