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ID PMID Title PublicationDate abstract
21326317 Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases. 2011 Apr The TNFAIP3 locus at 6q23, encoding A20, has been associated with multiple autoimmune diseases (AIDs). In this study, we sequence the coding portions of the gene to identify contributing causal polymorphisms that may explain some of the observed associations. A collection of 123 individuals from the Multiple Autoimmune Disease Genetics Consortium (MADGC) collection, each with multiple AIDs (mean=2.2 confirmed diagnoses), and 397 unrelated healthy controls were used for initial sequencing. A total of 32 polymorphisms were identified in the sequencing experiments, including 16 novel and 11 coding variants. Association testing in the entire MADGC collection (1,008 Caucasians with one or more AIDs and 770 unaffected family controls) revealed association of a novel intronic insertion-deletion polymorphism with rheumatoid arthritis (RA) (odds ratio (OR)=2.48, P=0.041). Genotyping of the most common coding polymorphism, rs2230926, in the MADGC collection and additional control individuals revealed a significant association with Sjögren's syndrome (OR=3.38, P=0.038), Crohn's disease (OR=2.25, P=0.041), psoriasis (OR=0.037, P=0.036) and RA (OR=1.9, P=0.025). Finally, haplotype and additional testing of polymorphisms revealed that cases were enriched for 5' and 3' untranslated region variants (one-sided P-value=0.04), but not specifically for common (>2% minor allele frequency), rare, exonic, intronic, non-synonymous or synonymous variants.
21121054 Visual integration of results from a large DNA biobank (BioVU) using synthesis-view. 2011 In this paper, we describe using Synthesis-View, a new method of presenting complex genetic data, to revisit results of a study from the BioVU Vanderbilt DNA databank. BioVU is a biorepository of DNA samples coupled with de-identified electronic medical records (EMR). In the Ritchie et al. study ~10,000 BioVU samples were genotyped for 21 SNPs that were previously associated with 5 diseases: atrial fibrillation, Crohn Disease, multiple sclerosis, rheumatoid arthritis, and type 2 diabetes. In the proof-of-concept study, the 21 tests of association replicated previous findings where sample size provided adequate power. The majority of the BioVU results were originally presented in tabular form. Herein we have revisited the results of this study using Synthesis-View. The Synthesis-View software tool visually synthesizes the results of complex, multi-layered studies that aim to characterize associations between small numbers of single-nucleotide polymorphisms (SNPs) and diseases and/or phenotypes, such as the results of replication and meta-analysis studies. Using Synthesis-View with the data of the Ritchie et al. study and presenting these data in this integrated visual format demonstrates new ways to investigate and interpret these kinds of data. Synthesis-View is freely available for non-commercial research institutions, for full details see https://chgr.mc.vanderbilt.edu/synthesisview.
21873531 An acquired defect in IgG-dependent phagocytosis explains the impairment in antibody-media 2011 Oct 1 B cells play important roles in autoimmune diseases ranging from multiple sclerosis to rheumatoid arthritis. B cells have also long been considered central players in systemic lupus erythematosus. However, anti-CD20-mediated B cell depletion was not effective in two clinical lupus studies, whereas anti-B lymphocyte stimulator, which inhibits B cell survival, was effective. Others and we previously found that anti-CD20-based depletion was surprisingly ineffective in tissues of lupus-prone mice, but that persistent high doses eventually led to depletion and ameliorated lupus. Lupus patients might also have incomplete depletion, as suggested in several studies, and which could have led to therapeutic failure. In this study, we investigated the mechanism of resistance to Ab-mediated cellular depletion in murine lupus. B cells from lupus-prone mice were easily depleted when transferred into normal environments or in lupus-prone mice that lacked serum Ig. Serum from lupus-prone mice transferred depletion resistance, with the active component being IgG. Because depletion is FcγR-dependent, we assayed macrophages and neutrophils exposed to lupus mouse serum, showing that they are impaired in IgG-mediated phagocytosis. We conclude that depletion resistance is an acquired, reversible phagocytic defect depending on exposure to lupus serum IgG. These results have implications for optimizing and monitoring cellular depletion therapy.
21862580 Akt fine-tunes NF-κB-dependent gene expression during T cell activation. 2011 Oct 14 Activation of the NF-κB signaling pathway is critical for leukocyte activation and development. Although previous studies suggested a role for the Akt kinase in coupling the T cell antigen receptor and CD28 to NF-κB activation in T cells, the nature of the role of Akt in this pathway is still unclear. Using a targeted gene profiling approach, we found that a subset of NF-κB-dependent genes required Akt for optimal up-regulation during T cell activation. The selective effects of Akt were manifest at the level of mRNA transcription and p65/RelA binding to upstream promoters and appear to be due to altered formation of the Carma1-Bcl10 complex. The proinflammatory cytokine TNF-α was found to be particularly sensitive to Akt inhibition or knockdown, including in primary human blood T cells and a murine model of rheumatoid arthritis. Our findings are consistent with a hierarchy in the expression of NF-κB-dependent genes, controlled by the strength and/or duration of NF-κB signaling. More broadly, our results suggest that defining the more graded effects of signaling, such as those demonstrated here for Akt and the NF-κB pathway, is important to understanding how cells can fine-tune signaling responses for optimal sensitivity and specificity.
21584310 Discovery of peptidylarginine deiminase-4 substrates by protein array: antagonistic citrul 2011 Jul Peptidylarginine deiminase (PAD) catalyzes the posttranslational citrullination of selected proteins in a calcium dependent manner. The PAD4 isoform has been implicated in multiple sclerosis, rheumatoid arthritis, some types of cancer, and plays a role in gene regulation. However, the substrate selectivity of PAD4 is not well defined, nor is the impact of citrullination on many other pathways. Here, a high-density protein array is used as a primary screen to identify 40 previously unreported PAD4 substrates, 10 of which are selected and verified in a cell lysate-based secondary assay. One of the most prominent hits, human 40S ribosomal protein S2 (RPS2), is characterized in detail. PAD4 citrullinates the Arg-Gly repeat region of RPS2, which is also an established site for Arg methylation by protein arginine methyltransferase 3 (PRMT3). As in other systems, crosstalk is observed; citrullination and methylation modifications are found to be antagonistic to each other, suggesting a conserved posttranslational regulatory strategy. Both PAD4 and PRMT3 are found to co-sediment with the free 40S ribosomal subunit fraction from cell extracts. These findings are consistent with participation of citrullination in the regulation of RPS2 and ribosome assembly. This application of protein arrays to reveal new PAD4 substrates suggests a role for citrullination in a number of different cellular pathways.
21566133 TLR2-dependent modulation of osteoclastogenesis by Porphyromonas gingivalis through differ 2011 Jul 8 Osteolytic diseases, including rheumatoid arthritis, osteomyelitis, and periodontitis, are usually associated with bacterial infections. However, the precise mechanisms by which bacteria induce bone loss still remain unclear. Evidence exists that Toll-like receptor (TLR) signaling regulates both inflammation and bone metabolism and that the receptor activator of NF-κB ligand (RANKL) and its receptor RANK are the key regulators for bone remodeling and for the activation of osteoclasts. Here, we investigate the direct effects of the periodontal pathogen Porphyromonas gingivalis on osteoclast differentiation and show that P. gingivalis differentially modulates RANKL-induced osteoclast formation contingent on the state of differentiation of osteoclast precursors. In addition, although an optimal induction of cytokines by P. gingivalis is dependent on TLR2 and TLR4, as well as myeloid differentiation factor 88 and Toll/IL-1R domain-containing adaptor-inducing IFN-β, P. gingivalis utilizes TLR2/ myeloid differentiation factor 88 in modulating osteoclast differentiation. P. gingivalis modulates RANKL-induced osteoclast formation by differential induction of NFATc1 and c-Fos. More importantly, RANKL-mediated lineage commitment also has an impact on P. gingivalis-induced cytokine production. RANKL inhibits P. gingivalis-induced cytokine production by down-regulation of TLR/NF-κB and up-regulation of NFATc1. Our findings reveal novel aspects of the interactions between TLR and RANK signaling and provide a new model for understanding the mechanism underlying the pathogenesis of bacteria-mediated bone loss.
21390242 The large zinc finger protein ZAS3 is a critical modulator of osteoclastogenesis. 2011 Mar 3 BACKGROUND: Mice deficient in the large zinc finger protein, ZAS3, show postnatal increase in bone mass suggesting that ZAS3 is critical in the regulation of bone homeostasis. Although ZAS3 has been shown to inhibit osteoblast differentiation, its role on osteoclastogenesis has not been determined. In this report we demonstrated the role of ZAS3 in bone resorption by examining the signaling mechanisms involved in osteoclastogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Comparison of adult wild-type and ZAS3 knockout (ZAS3-/-) mice showed that ZAS3 deficiency led to thicker bones that are more resistant to mechanical fracture. Additionally, ZAS3-/- bones showed fewer osteoclasts and inefficient M-CSF/sRANKL-mediated osteoclastogenesis ex vivo. Utilizing RAW 264.7 pre-osteoclasts, we demonstrated that overexpression of ZAS3 promoted osteoclastogenesis and the expression of crucial osteoclastic molecules, including phospho-p38, c-Jun, NFATc1, TRAP and CTSK. Contrarily, ZAS3 silencing by siRNA inhibited osteoclastogenesis. Co-immunoprecipitation experiments demonstrated that ZAS3 associated with TRAF6, the major receptor associated molecule in RANK signaling. Furthermore, EMSA suggested that nuclear ZAS3 could regulate transcription by binding to gene regulatory elements. CONCLUSION/SIGNIFICANCE: Collectively, the data suggested a novel role of ZAS3 as a positive regulator of osteoclast differentiation. ZAS3 deficiency caused increased bone mass, at least in part due to decreased osteoclast formation and bone resorption. These functions of ZAS3 were mediated via activation of multiple intracellular targets. In the cytoplasmic compartment, ZAS3 associated with TRAF6 to control NF-kB and MAP kinase signaling cascades. Nuclear ZAS3 acted as a transcriptional regulator for osteoclast-associated genes. Additionally, ZAS3 activated NFATc1 required for the integration of RANK signaling in the terminal differentiation of osteoclasts. Thus, ZAS3 was a crucial molecule in osteoclast differentiation, which might potentially serve as a target in the design of therapeutic interventions for the treatment of bone diseases related to increased osteoclast activity such as postmenopausal osteoporosis, Paget's disease, and rheumatoid arthritis.
23193618 (64)Cu-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-Arg-rich Cys knot scaffold 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3) and α(v)β(6). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Integrin α(v)β(6) plays an important role in the development of epithelial cells and is nearly undetectable on adult normal tissues. However, the levels of α(v)β(6) integrin can be upregulated during tissue remodeling and wound healing (11). On the other hand, α(v)β(6) integrin is strongly expressed on tumor cells of the oral cavity, pancreas, breast, ovary, colon, and stomach (12-14). α(v)β(6) integrin affects tumor growth, tumor invasiveness, and metastasis (13). α(v)β(6) binds to the RGD motif in fibronectin, tenascin, and the viral protein 1 (VP1) of foot-and-mouth disease virus (FMDV) (15). FMDV binds to cells through the RGD motif of the GH loop of the VP1. A consensus α(v)β(6)-binding motif DLXXL was identified by using phage display screening with minimal binding to α(v)β(3), α(IIb)β(3), and α(v)β(5) (16). Engineered cysteine knot peptides (knots) comprise a rigid molecular scaffold of ~4 kDa with three disulfide bonds and a centrally located β sheet. Kimura et al. (17) grafted a α(v)β(6)-binding peptide (RSLARTDLDHLRGR) into the loop 1 of an Arg-rich knot to produce the knot known as R(0)2, which was radiolabeled with (64)Cu via 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugation to form (64)Cu-DOTA-R(0)2 as a positron emission tomography (PET) probe for in vivo imaging of α(v)β(6) integrin in tumor-bearing nude mice.
22776094 The SYK side of TLR4: signalling mechanisms in response to LPS and minimally oxidized LDL. 2012 Nov Spleen tyrosine kinase (SYK) is the best known for its involvement in immune receptor signalling, mediated by binding of SYK tandem Src-homology 2 domains to tandem phosphotyrosine in immunoreceptor tyrosine-based activation motifs (ITAMs). ITAM adaptors or ITAM-containing receptor tails mediate signalling from B- and T-cell receptors, Fc receptors and many C-type lectins, including dectin-1. Recent data point to constitutive binding of SYK to the cytoplasmic domain of toll-like receptor-4 (TLR4). This SYK-TLR4 binding increases upon TLR4 dimerization and phosphorylation, and SYK plays a prominent role in TLR4 signalling in response to LPS in neutrophils and monocytes. SYK also plays an important role in TLR4-mediated macrophage responses to minimally oxidized low-density lipoprotein (mmLDL), which is a form of oxidized LDL relevant to development of human atherosclerosis. Interestingly, mmLDL-induced effects in macrophages, which occur via TLR4, are predominantly MyD88 independent. This unmasks the role of the SYK branch of TLR4 signalling, which mediates modest cytokine release via activation of AP-1 transcription and robust reactive oxygen species generation and cytoskeletal rearrangements. The latter results in extensive membrane ruffling and macropinocytosis, leading to lipoprotein uptake and foam cell formation, a hallmark of atherosclerotic lesions. Because inhibitors of SYK activity, such as fostamatinib, are in advanced clinical trials for rheumatoid arthritis and other autoimmune diseases, understanding the role of SYK in signalling via TLR4 is of immediate importance. This signalling pathway seems to be particularly important in TLR4 activation by host-derived, damage-associated molecular pattern ligands, such as mmLDL, relevant to development of atherosclerosis and other chronic inflammatory diseases.
22483552 Cardioprotective effect of total paeony glycosides against isoprenaline-induced myocardial 2012 Jun 15 Paeoniae radix is a traditional Chinese medicinal herb for treating some diseases; important components are total paeony glycosides (TPGs), an approved drug by the State Food and Drug Administration (SFDA) for the therapy of rheumatoid arthritis (RA). We firstly reported myocardial benefits of TPGs previously, and the present study is to further investigate the underlying mechanisms for preventing oxidative damage in cardiomyopathy. We measured the capacity of TPGs to scavenge free radicals in vitro. Then 60 SD rats were randomly divided into five groups: (1) a normal control group, (2) an isoprenaline (ISO)-induced myocardial ischemic model group, (3) a TPG treatment group (TPGs 269.4 mg/kg delivered by intragastric administration for 3 days before ISO administration and TPGs 449 mg/kg delivered for 3 days after ISO administration), (4) a TPG therapy group (TPGs 449 mg/kg delivered for 3 days after ISO administration), and (5) a positive control group (propranolol 15 mg/kg for 3 days after ISO administration). The ISO-induced myocardial ischemic model was established by subcutaneous injection of 1mg/kg/8h ISO (2 times). The activities of myocardial enzymes, including glutamic oxaloacetic transaminase (GOT), creatine kinase (CK), lactate dehydrogenase (LDH), antioxidant enzyme superoxide dismutase (SOD) as well as the content of lipid peroxidation product malondialdehyde (MDA) were detected. We found that TPGs potently eliminated hydroxyl radicals and superoxide in vitro using ESR assays. Compared with model rats, TPG treatment, TPG therapy and the positive control treatment exhibited significantly reduced activities of GOT, LDH, and CK (p < 0.01), increased activity of SOD (p < 0.01) and lower levels of MDA (p < 0.05). More interestingly, the protective effect of TPG treatment was even better than that of propranolol. These results suggest that TPGs significantly ameliorate ISO-induced myocardial ischemia and their action might be through reducing oxidative stress in ischemic myocardium.
22447223 Sirt1 overexpression protects murine osteoblasts against TNF-α-induced injury in vitro by 2012 May AIM: Sirtuin 1 (Sirt1) is the class III histone/protein deacetylase that interferes with the NF-κB signaling pathway, thereby has anti-inflammatory function. This study was undertaken to investigate whether Sirt1 could protect osteoblasts against TNF-α-induced injury in vitro. METHODS: Murine osteoblastic cell line, MC3T3-E1, was used. Overexpress of Sirt1 protein in MC3T3-E1 cells was made by transfection the cells with Sirt1-overexpressing adenovirus. The levels of mRNAs and proteins were determined with qRT-PCR and Western blotting, respectively. The activity of NF-κB was examined using NF-κB luciferase assay. The NO concentration was measured using the Griess method. RESULTS: Treatment of MC3T3-E1 cells with TNF-α (2.5-10 ng/mL) suppressed Sirt1 protein expression in a concentration-dependent manner. TNF-α (5 ng/mL) resulted in an increase in apoptosis and a reduction in ALP activity in the cells. Overexpression of Sirt1 in the cells significantly attenuated TNF-α-induced injury through suppressing apoptosis, increasing ALP activity, and increasing the expression of Runx2 and osteocalcin mRNAs. Furthermore, overexpression of Sirt1 in the cells significantly suppressed TNF-α-induced NF-κB activation, followed by reducing the expression of iNOS and NO formation. Sirt1 activator resveratrol (10 μmol/L) mimicked the protection of the cells by Sirt1 overexpression against TNF-α-induced injury, which was reversed by the Sirt1 inhibitor EX-527 (5 μmol/L). CONCLUSION: Overexpression of Sirt1 protects MC3T3-E1 osteoblasts aganst TNF-α-induced cell injury in vitro, at least in part, via suppressing NF-κB signaling. Sirt1 may be a novel therapeutic target for treating rheumatoid arthritis-related bone loss.
22371149 G protein-coupled adenosine (P1) and P2Y receptors: ligand design and receptor interaction 2012 Sep The medicinal chemistry and pharmacology of the four subtypes of adenosine receptors (ARs) and the eight subtypes of P2Y receptors (P2YRs, activated by a range of purine and pyrimidine mono- and dinucleotides) has recently advanced significantly leading to selective ligands. X-ray crystallographic structures of both agonist- and antagonist-bound forms of the A(2A)AR have provided unprecedented three-dimensional detail concerning molecular recognition in the binding site and the conformational changes in receptor activation. It is apparent that this ubiquitous cell signaling system has implications for understanding and treating many diseases. ATP and other nucleotides are readily released from intracellular sources under conditions of injury and organ stress, such as hypoxia, ischemia, or mechanical stress, and through channels and vesicular release. Adenosine may be generated extracellularly or by cellular release. Therefore, depending on pathophysiological factors, in a given tissue, there is often a tonic activation of one or more of the ARs or P2YRs that can be modulated by exogenous agents for a beneficial effect. Thus, this field has provided fertile ground for pharmaceutical development, leading to clinical trials of selective receptor ligands as imaging agents or for conditions including cardiac arrhythmias, ischemia/reperfusion injury, diabetes, pain, thrombosis, Parkinson's disease, rheumatoid arthritis, psoriasis, dry eye disease, pulmonary diseases such as cystic fibrosis, glaucoma, cancer, chronic hepatitis C, and other diseases.
22258781 Risk factors for pulmonary embolism and the effects of fondaparinux after total hip and kn 2011 Dec 21 BACKGROUND: Clinical evidence demonstrating the effectiveness of pharmacological and mechanical thromboprophylaxis for the prevention of pulmonary embolism is limited because the prevalence of postoperative pulmonary embolism following total hip and knee arthroplasty is very low. Our purposes were to characterize a patient population with in-hospital pulmonary embolism, to identify perioperative risk factors associated with pulmonary embolism, and to analyze the effect of combining fondaparinux with mechanical prophylaxis on the prevalence of pulmonary embolism following total hip and knee arthroplasty. METHODS: We retrospectively identified 27,542 patients who underwent total hip or knee arthroplasty at 793 hospitals, using data from the Diagnosis Procedure Combination database, collected from July 1 to December 31 in 2007 and 2008. We extracted data on patient sex, age, primary diagnoses, and comorbidities that could potentially affect the prevalence of pulmonary embolism. The dates of pharmacological and mechanical thromboprophylaxis were identified for each patient. Logistic regression analysis was performed to analyze the concurrent effects of various factors on the prevalence of postoperative pulmonary embolism. RESULTS: The mean age (and standard deviation) of the patients at the time of arthroplasty was 69.9 ± 10.3 years, and 23,783 patients (86.4%) were diagnosed as having osteoarthritis. The overall mean duration of anesthesia was 159 ± 84 minutes. The overall prevalence of postoperative pulmonary embolism was 0.55% (151 of 27,542). Significant risk factors for postoperative pulmonary embolism included age, number of comorbidities, diagnosis of rheumatoid arthritis, type of anesthesia, and duration of anesthesia. Multivariate analysis found that the prevalence of postoperative pulmonary embolism was significantly reduced when fondaparinux was used in combination with mechanical prophylaxis, compared with the use of mechanical prophylaxis alone (0.40% versus 0.66%; odds ratio, 0.60; 95% confidence interval, 0.42 to 0.84; p = 0.003). CONCLUSIONS: These findings could help to identify patients at higher risk of postoperative pulmonary embolism after total hip or knee arthroplasty. Our results demonstrate the effectiveness of fondaparinux in combination with mechanical prophylaxis for the prevention of postoperative pulmonary embolism after total hip or knee arthroplasty.
22238453 Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in 2012 Feb 15 IL-20 is a proinflammatory cytokine involved in rheumatoid arthritis, atherosclerosis, and stroke. However, little is known about its role in breast cancer. We explored the function of IL-20 in tumor growth and metastasis, as well as in clinical outcome. Tumor expression of IL-20 was assessed by immunohistochemical staining among 198 patients with invasive ductal carcinoma of the breast, using available clinical and survival data. IL-20 expression was associated with advanced tumor stage, greater tumor metastasis, and worse survival. Reverse transcription quantitative polymerase chain reaction showed that clinical breast tumor tissue expressed higher levels of IL-20 and its receptors than did nontumorous breast tissue. IL-20 was also highly expressed in breast cancer bone-metastasis tissue. In vitro, IL-20 upregulated matrix metalloproteinase-9, matrix metalloproteinase-12, cathepsin K, and cathepsin G, and enhanced proliferation and migration of breast cancer cells, which were inhibited by anti-IL-20 mAb 7E. In vivo, we generated murine models to evaluate the therapeutic potential of 7E, using luminescence intensity, radiological scans, and micro-computed tomography. 7E reduced tumor growth, suppressed bone colonization, diminished tumor-mediated osteolysis, and lessened bone density decrement in mice injected with breast cancer cells. In conclusion, our results suggest that IL-20 plays pivotal roles in the tumor progression of breast cancer. IL-20 expression in breast cancer tissue is associated with a poor clinical outcome. Anti-IL-20 mAb 7E suppressed bone colonization and decreased osteolytic bone lesions. Therefore, IL-20 may be a novel target in treating breast tumor-induced osteolysis.
22019508 Anti-inflammatory activities and mechanisms of action of the petroleum ether fraction of R 2011 Dec 8 ETHNOPHARMACOLOGICAL RELEVANCE: The hip of Rosa multiflora Thunb. has been traditionally used as a dietary supplement and a herbal remedy for the treatment of various diseases including cold, flu, inflammation, osteoarthritis, rheumatoid arthritis and chronic pain in China. AIMS OF THE STUDY: To explore the anti-inflammatory ingredient of the hip of R. multiflora Thunb. and its mechanism of action. MATERIALS AND METHODS: The ethanol extract of the hip of R. multiflora Thunb. was fractioned with petroleum ether, ethyl acetate and water, and each fraction was screened for anti-inflammatory activity in xylene-induced mouse ear edema model. Three more models, acetic acid-induced mouse vascular permeation, cotton pellet-induced rat granuloma, and carrageenan-induced rat hind paw edema were also employed to verify the anti-inflammatory effect of the identified fraction. To explore the mechanism of action, the activity of inducible nitric oxide synthase (iNOS) and the level of nitric oxide (NO) in sera, as well as mRNA expression level of cyclo-oxygenase-2 (COX-2) in inflammatory tissues of rats with carrageenan-induced hind paw edema were measured. GC-MS technology was applied to identify the active components in the active fraction. RESULTS AND CONCLUSIONS: The petroleum ether fraction (PEF) was identified to be the active fraction in inflammation animal models (i.e., oral administration of PEF (168.48, 42.12 and 10.53 mg/kg) evoked a significantly (P<0.001) dose-dependent inhibition of the xylene-induced mice ear edema). Down-regulating COX-2 expression (P<0.001) and reducing NO production (P<0.05) through inhibiting iNOS activity (P<0.001) may be the partial mechanism of action of PEF. GC-MS analysis indicated that unsaturated fatty acids are enriched in PEF and may be responsible for the anti-inflammatory activity of PEF and this herb. The results of this study provide pharmacological and chemical basis for the application of the hip of R. multiflora Thunb. in inflammatory disorders.
20422155 Bone health-related factors and the use of bisphosphonates in community setting--15-year f 2011 Jan The present study investigated the bone health related factors that were associated with the use of bisphosphonates (BP) among 2,050 postmenopausal Finnish women. Low BMD + low trauma energy fracture was the strongest determinant of BP use, while other secondary causes of osteoporosis were less strongly related with BP use. BP use was associated with reduced femoral neck (FN) and lumbar spine (LS) bone loss rate. INTRODUCTION: The aim was to identify bone health related factors associated with the use of BP in a community setting. METHODS: A population-based sample of 2,050 Finnish postmenopausal women was measured with dual X-ray absorptiometry at the FN and LS in 1989, 1994, 1999 and 2004, and information on osteoporosis risk factors, including low-trauma energy fractures, were collected with postal inquiries. Self-reported use of BP in 2004 was considered as the end point variable. RESULTS: Among BP users, 12% had T-score > -2.0 SD and no fracture during follow-up (FU). In women without any bone medication, 26% had T-score < -2.0 SD or low-trauma energy fracture or both during the FU. In BP users, a significant reduction in FN and LS bone loss rate, cumulative with duration of use, was observed in ANCOVA (p < 0.001). Among BP users, there was a significantly higher proportion of women with several independent risk factors for osteoporosis and more spine and humerus fractures but less ankle fractures. T-score < -2 SD combined with low-trauma energy fracture was significantly related to the use of BPs (p < 0.001, OR = 15.96) and T-score < -2 SD was a stronger predictor of BP use (p < 0.001, OR = 13.29) than fracture (p > 0.05, OR = 1.35) in multivariate logistic regression. Other factors related with BP use were vitamin D use (p = 0.001, OR = 2.27), high number of medications (p < 0.001, OR = 1.26) and rheumatoid arthritis (p < 0.05, OR 2.55). CONCLUSIONS: These findings reveal the recent bone health-related indications for BP prescription.
30742399 Flurbiprofen Therapy and CYP2C9 Genotype. 2012 Flurbiprofen (brand name Ansaid) is a nonsteroidal anti-inflammatory drug (NSAID). Tablets and skin patches are used in the management of osteoarthritis and rheumatoid arthritis. Flurbiprofen provides pain relief and reduces inflammation. Flurbiprofen eye drops (brand name Ocufen) may also be used to prevent miosis (excessive constriction of the pupil) during eye operations; e.g., cataract surgery. Flurbiprofen is primarily metabolized by CYP2C9. Individuals who lack CYP2C9 activity (CYP2C9 poor metabolizers) have an increased exposure to flurbiprofen, and an increased risk of side effects. Like all NSAIDs, flurbiprofen increases the risk of serious cardiovascular events, including myocardial infarction and stroke, and serious gastrointestinal (GI) adverse events such as bleeding, ulceration, and perforation, which may be fatal. The recommended starting dose of flurbiprofen tablets in adults is 200–300 mg per day, divided for administration 2, 3, or 4 times a day. But for all patients, the lowest effective dose of flurbiprofen should be used for the shortest length of time, consistent with the treatment goals of each individual. The FDA-approved drug label for flurbiprofen states that the dose of flurbiprofen should be reduced in “patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin)” (Table 1). This dose reduction is to avoid the abnormally high plasma levels of flurbiprofen in these patients caused by reduced metabolic clearance. However, specific dose reductions based on CYP2C9 phenotype are not provided (1). As for all NSAIDs, flurbiprofen is contraindicated in patients with a known hypersensitivity; a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or another NSAID; and for coronary artery bypass graft (CABG) surgery. Flurbiprofen should also be avoided by pregnant women starting at 30 weeks gestation (1).
23193616 (111)In-Diethylenetriamine pentaacetic acid-NAVPNLRGDLQVLAQKVART. 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3) and α(v)β(6). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). The α(v)β(6) integrin plays an important role in the development of epithelial cells and is nearly undetectable on normal adult tissues. However, the levels of α(v)β(6) integrin can be upregulated during tissue remodeling and wound healing (11). On the other hand, α(v)β(6) integrin is strongly expressed on tumor cells of the oral cavity, pancreas, breast, ovary, colon, and stomach (12-14). α(v)β(6) integrin affects tumor growth, tumor invasiveness, and metastasis (13). α(v)β(6) binds to the RGD motif in fibronectin, tenascin, and the viral protein 1 (VP1) of the foot-and-mouth disease virus (FMDV) (15). FMDV binds to cells through the RGD motif of the GH loop of the VP1. The consensus α(v)β(6)-binding motif DLXXL was identified with the use of phage display screening, with minimal binding to α(v)β(3), α(IIb)β(3), and α(v)β(5) (16). A 20-amino acid peptide, NAVPNLRGDLQVLAQKVART (A20FMDV2), was identified as a ligand binding to α(v)β(6) integrin (15). A20FMDV2 was radiolabeled with N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) to study in vivo biodistribution of the tracer in tumor-bearing mice (17). [(18)F]FB-A20FMDV2 was found to have specific accumulation in α(v)β(6)-positive tumors. For single-photon emission computed tomography (SPECT), Saha et al. (18) prepared (111)In-diethylenetriamine pentaacetic acid-A20FMDV2 ((111)In-DTPA-A20FMDV2) for in vivo imaging of α(v)β(6)-positive tumors.
23166958 (99m)Tc-Hydrazinonicotinyl(tricine)(TPPTS)-Glu-c(RGDyK)-bombesin[7-14]NH(2). 2004 The amphibian bombesin (BBN or BN, a peptide of 14 amino acids) is an analog of human gastrin-releasing peptide (GRP, a peptide of 27 amino acids) that binds to GRP receptors (GRPR) with high affinity and specificity (1, 2). Both GRP and BBN share an amidated C-terminus sequence homology of seven amino acids, Trp-Ala-Val-Gly-His-Leu-Met-NH(2). BBN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system. They also act as potential growth factors for both normal and neoplastic tissues (3). Specific BBN receptors (BBN-Rs) have been identified on CNS and GI tissues and on a number of tumor cell lines (4). The BBN-R superfamily includes at least four different subtypes, namely the GRPR subtype (BB2), the neuromedin B receptor subtype (BB1), the BB3 subtype, and the BB4 subtype. The findings of GRPR overexpression in various human tumors, such as breast, prostate, lung, colon, ovarian, and pancreatic cancers, provide opportunities for tumor imaging by designing specific molecular imaging agents to target the GRPR (5, 6). Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (7). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (8-13). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. A peptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various ligands have been introduced for imaging of tumors and tumor angiogenesis (14). Because breast and prostate cancers express both GRPR and α(v)β(3), Liu et al. (15) designed an RGD-BBN heterodimer in which BBN[7-14]NH(2) and c(RGDyK) are connected with a glutamate linker (BBN on the Glu side chain γ-carboxylate group and RGD on the Glu side chain α-carboxylate group). 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) was used as a bifunctional chelator for labeling RGD-BBN to form (64)Cu-NOTA-RGD-BBN for use in positron emission tomography (PET) imaging of α(v)β(3) and GRPR in nude mice bearing human tumors. For single-photon emission computed tomography (SPECT), Liu et al. (16) conjugated Glu-RGD-BBN with 6-hydrazinonicotinyl (HYNIC) and labeled the product with (99m)Tc, using tricine and trisodium triphenylphosphine-trisulfonate (TPPTS) as the coligands. (99m)Tc-HYNIC-RGD-BBN was evaluated in C57/BL6 mice bearing mouse Lewis lung carcinomas (LLC).
23166957 (64)Cu-1,4,7-Triazacyclononane-1,4-diacetic acid-c(RGDyK)-Glu-6-aminohexanoic acid-bombesi 2004 The amphibian bombesin (BBN or BN, a peptide of 14 amino acids) is an analog of human gastrin-releasing peptide (GRP, a peptide of 27 amino acids) that binds to GRP receptor (GRPR) with high affinity and specificity (1, 2). Both GRP and BBN share an amidated C-terminus sequence homology of seven amino acids, Trp-Ala-Val-Gly-His-Leu-Met-NH(2). BBN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system. They also act as potential growth factors for both normal and neoplastic tissues (3). Specific BBN receptors (BBN-Rs) have been identified on CNS and GI tissues and on a number of tumor cell lines (4). The BBN-R superfamily includes at least four different subtypes, namely the GRPR subtype (BB2), the neuromedin B receptor subtype (BB1), the BB3 subtype, and the BB4 subtype. The findings of GRPR overexpression in various human tumors, such as breast, prostate, lung, colon, ovarian, and pancreatic cancers, provide opportunities for tumor imaging by designing specific molecular imaging agents to target the GRPR (5, 6). Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (7). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (8-13). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. A peptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various ligands have been introduced for imaging of tumors and tumor angiogenesis (14). Because breast and prostate cancers express both GRPR and α(v)β(3), Jackson et al. (15) designed an RGD-BBN heterodimer in which c(RGDyK) and BBN[7-14]NH(2) are connected with a glutamate linker (BBN on the Glu side chain γ-carboxylate group and RGD on the Glu side chain α-carboxylate group). A spacer, 6-aminohexanoic acid (6-Ahx), was put onto the glutamate α-amino group of RGD-Glu-BBN to increase the hydrophilicity and to relieve the steric hindrance. 1,4,7-Triazacyclononane-1,4-7-triacetic acid (NOTA) was used as a bifunctional chelator for labeling RGD-BBN to form (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN for use in positron emission tomography (PET) imaging of α(v)β(3) and GRPR in nude mice bearing human tumors.