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2013年5月25日星期六

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

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Intracoronary Optical Coherence Tomography and Histology of Overlapping Everolimus-Eluting Bioresorbable Vascular Scaffolds in a Porcine Coronary Artery Model: The Potential Implications for Clinical Practice.

Intracoronary Optical Coherence Tomography and Histology of Overlapping Everolimus-Eluting Bioresorbable Vascular Scaffolds in a Porcine Coronary Artery Model: The Potential Implications for Clinical Practice.

JACC Cardiovasc Interv. 2013 May;6(5):523-532

Authors: Farooq V, Serruys PW, Heo JH, Gogas BD, Onuma Y, Perkins LE, Diletti R, Radu MD, R�ber L, Bourantas CV, Zhang Y, van Remortel E, Pawar R, Rapoza RJ, Powers JC, van Beusekom HM, Garc�a-Garc�a HM, Virmani R

Abstract
OBJECTIVES: This study sought to assess the vascular response of overlapping Absorb stents compared with overlapping newer-generation everolimus-eluting metallic platform stents (Xience V [XV]) in a porcine coronary artery model. BACKGROUND: The everolimus-eluting bioresorbable vascular scaffold (Absorb) is a novel approach to treating coronary lesions. A persistent inflammatory response, fibrin deposition, and delayed endothelialization have been reported with overlapping first-generation drug-eluting stents. METHODS: Forty-one overlapping Absorb and overlapping Xience V (XV) devices (3.0 � 12 mm) were implanted in the main coronary arteries of 17 nonatherosclerotic pigs with 10% overstretch. Implanted coronary arteries were evaluated by optical coherence tomography (OCT) at 28 days (Absorb n = 11, XV n = 7) and 90 days (Absorb n = 11, XV n = 8), with immediate histological evaluation following euthanasia at the same time points. One animal from each time point was evaluated with scanning electron microscopy alone. A total of 1,407 cross sections were analyzed by OCT and 148 cross sections analyzed histologically. RESULTS: At 28 days in the overlap, OCT analyses indicated 80.1% of Absorb struts and 99.4% of XV struts to be covered (p < 0.0001), corresponding to histological observations of struts with cellular coverage of 75.4% and 99.6%, respectively (p < 0.001). Uncovered struts were almost exclusively related to the presence of "stacked" Absorb struts, that is, with a direct overlay configuration. At 90 days, overlapping Absorb and overlapping XV struts demonstrated >99% strut coverage by OCT and histology, with no evidence of a significant inflammatory process, and comparable % volume obstructions. CONCLUSIONS: In porcine coronary arteries implanted with overlapping Absorb or overlapping XV struts, strut coverage is delayed at 28 days in overlapping Absorb, dependent on the overlay configuration of the thicker Absorb struts. At 90 days, both overlapping Absorb and overlapping XV have comparable strut coverage. The implications of increased strut thickness may have important clinical and design considerations for bioresorbable platforms.

PMID: 23702016 [PubMed - as supplied by publisher]

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Fracture risk after thiazide-associated hyponatraemia.

Fracture risk after thiazide-associated hyponatraemia.

Intern Med J. 2012 Jul;42(7):760-4

Authors: Chow KM, Szeto CC, Kwan BC, Ma TK, Leung CB, Li PK

Abstract
BACKGROUND/AIM: Although thiazide-type diuretics can promote a positive calcium balance, thiazide can be associated with hyponatraemia, which is recently linked with heightened fracture risk. We examine the chance of developing fracture in patients with and without hyponatraemia after taking thiazide diuretics.
METHODS: In this single-centre retrospective study, we followed up a previously published cohort of patients with (n= 223) and without (n= 216) thiazide-induced hyponatraemia.
RESULTS: A total of 61 osteoporotic fractures was recorded during a mean follow-up period of 82 months. Using univariate regression analysis, the hazard ratio of thiazide-induced hyponatraemia was 1.78 (95% confidence interval (CI), 1.05-3.03; P= 0.033). Cox proportional hazards regression analysis, however, showed that age, body mass index and diabetes mellitus were the only independent predictors of osteoporotic fractures. No association of a history of thiazide-induced hyponatraemia and risk of fracture was evident in the final model.
CONCLUSION: Since a history of thiazide-induced hyponatraemia is associated with osteoporotic fracture in univariate but not multivariate analyses, an alternative explanation is that confounding factors of older age and low body mass index accounted for the apparently increased risk of osteoporotic fracture in patients with thiazide-induced hyponatraemia.

PMID: 22150918 [PubMed - indexed for MEDLINE]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

Abstract
Automated multicolor fluorescence microscopy facilitates high-throughput quantitation of cellular parameters of complex, organotypic systems. In vitro co-cultured vascular cells form capillary-like networks that model facets of angiogenesis, making it an attractive alternative for anti-angiogenic drug discovery. We have adapted this angiogenesis assay system to a high-throughput format to enable automated image-based high-throughput screening of live primary human vascular cell co-cultures with chemical libraries for anti-angiogenic drug discovery. Protocols are described for setup of a fluorescence-based co-culture assay, live cell image acquisition, image analysis of morphological parameters, and screening data handling.

PMID: 23027002 [PubMed - indexed for MEDLINE]

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The glutathione-related detoxication responses to juvenile and ecdysone hormones in Galleria mellonella.

The glutathione-related detoxication responses to juvenile and ecdysone hormones in Galleria mellonella.

Comp Biochem Physiol C Toxicol Pharmacol. 2013 May 14;

Authors: Tarhan L, Kayal? HA, Karacali S, Y?k?lmaz S

Abstract
The effect of 20-hydroxyecdysone (20E) and juvenile hormone (JH) on the glutathione pathway of the greater wax moth G. mellonella (Lepidoptera. Pyralidae) was determined by investigating glutathione peroxidase (GSH-Px), glutathione S-transferases (GST), and glutathione reductase (GR) activities as well as reduced and oxidized glutathione (GSH and GSSG) content with respect to developmental stage. The continuous decreases of GSH-Px and GST activities dependent on the growth period of G. mellonella occurred in JH and 20E groups over and under their controls, respectively. While the GR activities of G. mellonella showed increases in young pupa (YP) for both control and in old larvae (OL) for the 20E groups after the minimum at these periods, they also increased after old pupa (OP) for the JH group with a maximum in OL period. Although GR activity levels in the JH group were significantly higher compared to controls and 20E groups up to OP period, the activity levels for the control and 20E groups were higher than those of the JH group at adult (AD) and old pupa (OP) periods, respectively. In spite of increases in the GR activity of 20E and control groups of G. mellonella, decreased GSH and increased GSSG levels were observed at aging period. GSH levels in the JH group reached a maximum at prepupa (PP) and then decreased with non-significant changes from OL to AD period. According to the results, GSH and GSSG levels, as well as GSH/GSSG ratios, were below and over control levels in 20E and JH groups, respectively, during all of the investigated developmental stages. On the contrary, the LPO levels were higher than control for 20E and lower for JH groups during the developmental period. These results show that while ecdysone hormone has a negative effect on the glutathione-related detoxication capacity of G. mellonella, juvenile hormone has a positive effect on this process.

PMID: 23684736 [PubMed - as supplied by publisher]

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2013年5月24日星期五

Everolimus: A Guide to Its Use in Liver Transplantation.

Everolimus: A Guide to Its Use in Liver Transplantation.

BioDrugs. 2013 May 22;

Authors: Keating GM, Lyseng-Williamson KA

Abstract
The mammalian target of rapamycin inhibitor everolimus (Zortress(�), Certican(�)) was recently approved in the USA and a number of EU countries for use in combination with a reduced dosage of tacrolimus and corticosteroids for the prophylaxis of organ rejection in adult liver transplant recipients. Compared with standard-exposure tacrolimus, early use of everolimus plus a reduced dosage of tacrolimus did not compromise efficacy in liver transplant recipients. In addition, significantly better renal function with everolimus plus reduced-exposure tacrolimus than with standard-exposure tacrolimus was seen from 6�weeks post-transplant onwards. Everolimus plus reduced-exposure tacrolimus has an acceptable tolerability profile in liver transplant recipients.

PMID: 23696253 [PubMed - as supplied by publisher]

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Expression of the RNA Helicase DDX3 and the Hypoxia Response in Breast Cancer.

Expression of the RNA Helicase DDX3 and the Hypoxia Response in Breast Cancer.

PLoS One. 2013;8(5):e63548

Authors: Bol GM, Raman V, van der Groep P, Vermeulen JF, Patel AH, van der Wall E, van Diest PJ

Abstract
AIMS: DDX3 is an RNA helicase that has antiapoptotic properties, and promotes proliferation and transformation. In addition, DDX3 was shown to be a direct downstream target of HIF-1? (the master regulatory of the hypoxia response) in breast cancer cell lines. However, the relation between DDX3 and hypoxia has not been addressed in human tumors. In this paper, we studied the relation between DDX3 and the hypoxic responsive proteins in human breast cancer.
METHODS AND RESULTS: DDX3 expression was investigated by immunohistochemistry in breast cancer in comparison with hypoxia related proteins HIF-1?, GLUT1, CAIX, EGFR, HER2, Akt1, FOXO4, p53, ER?, COMMD1, FER kinase, PIN1, E-cadherin, p21, p27, Transferrin receptor, FOXO3A, c-Met and Notch1. DDX3 was overexpressed in 127 of 366 breast cancer patients, and was correlated with overexpression of HIF-1? and its downstream genes CAIX and GLUT1. Moreover, DDX3 expression correlated with hypoxia-related proteins EGFR, HER2, FOXO4, ER? and c-Met in a HIF-1? dependent fashion, and with COMMD1, FER kinase, Akt1, E-cadherin, TfR and FOXO3A independent of HIF-1?.
CONCLUSIONS: In invasive breast cancer, expression of DDX3 was correlated with overexpression of HIF-1? and many other hypoxia related proteins, pointing to a distinct role for DDX3 under hypoxic conditions and supporting the oncogenic role of DDX3 which could have clinical implication for current development of DDX3 inhibitors.

PMID: 23696831 [PubMed - in process]

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From first to second generation drug eluting stents for treatment of coronary bifurcations: are we making progress?

From first to second generation drug eluting stents for treatment of coronary bifurcations: are we making progress?

Catheter Cardiovasc Interv. 2012 Dec 1;80(7):1171-2

Authors: Diletti R, Serruys P

PMID: 23225655 [PubMed - indexed for MEDLINE]

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DNA damage and transcriptional changes induced by tributyltin (TBT) after short in vivo exposures of Chironomus riparius (Diptera) larvae.

DNA damage and transcriptional changes induced by tributyltin (TBT) after short in vivo exposures of Chironomus riparius (Diptera) larvae.

Comp Biochem Physiol C Toxicol Pharmacol. 2013 May 14;

Authors: Morales M, Mart�nez-Paz P, Oz�ez I, Mart�nez-Guitarte JL, Morcillo G

Abstract
Tributyltin (TBT) is a widespread environmental contaminant in aquatic systems whose adverse effects in development and reproduction are related to its well-known endocrine-disrupting activity. In this work, the early molecular effects of TBT in Chironomus riparius (Diptera) were evaluated by analysing its DNA damaging potential and the transcriptional response of different endocrine-related genes. Twenty-four-hour in vivo exposures of the aquatic larvae, at environmentally relevant doses of TBT, revealed genotoxic activity as shown by significant increases in DNA strand breaks quantified with the comet assay. TBT was also able to induce significant increases in transcripts from the ecdysone receptor gene (EcR), the ultraspiracle gene (usp) (insect ortholog of the retinoid X receptor), the estrogen-related receptor (ERR) gene and the E74 early ecdysone-inducible gene, as measured by Real time RT-PCR. In contrast, the expression of the vitellogenin (vg) gene remained unaltered, while the hsp70 gene appeared to be downregulated. The ability of TBT to upregulate hormonal target genes provides the first evidence, at genomic level, of its endocrine disruptive effects, and also suggests a mechanism of action that mimics ecdysteroid hormones in insects. These data reveal for the first time the early genomic effects of TBT on an insect genome.

PMID: 23684738 [PubMed - as supplied by publisher]

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2013年5月23日星期四

From first to second generation drug eluting stents for treatment of coronary bifurcations: are we making progress?

From first to second generation drug eluting stents for treatment of coronary bifurcations: are we making progress?

Catheter Cardiovasc Interv. 2012 Dec 1;80(7):1171-2

Authors: Diletti R, Serruys P

PMID: 23225655 [PubMed - indexed for MEDLINE]

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Image-based high-throughput screening for inhibitors of angiogenesis.

Image-based high-throughput screening for inhibitors of angiogenesis.

Methods Mol Biol. 2013;931:139-51

Authors: Evensen L, Link W, Lorens JB

PMID: 23027002 [PubMed - indexed for MEDLINE]

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Recent advances in the treatment of metastatic renal cell carcinoma.

Recent advances in the treatment of metastatic renal cell carcinoma.

Int J Urol. 2013 May 21;

Authors: Abe H, Kamai T

Abstract
In the past 5 years, the treatment of patients with metastatic renal cell carcinoma has changed dramatically from being largely cytokine-based with the emergence of targeted therapy. Following the elucidation of various molecular pathways in renal cell carcinoma, targeted agents (particularly vascular endothelial growth factor-targeting antiangiogenic agents) now form the backbone of most therapeutic strategies for patients with metastatic renal cell carcinoma and the outcome of treatment has improved. However, many tumors eventually develop resistance to targeted therapy due to secondary mutation of the target protein or compensatory changes within the target pathway that bypass the site of inhibition. On the other hand, there are new forms of immunotherapy that hold the promise of improving the outcome for patients with metastatic renal cell carcinoma. In this article, we describe some of these new therapies, including the anti-vascular endothelial growth factor monoclonal antibody bevacizumab, several receptor tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, axitinib, and tivozanib), the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and new immunotherapy modalities, such as anti-cytotoxic T-lymphocyte-associated antigen?4 antibody and anti-programmed cell death?1/programmed cell death-ligand?1 antibody. We also discuss their role in the current management of patients with metastatic renal cell carcinoma.

PMID: 23692504 [PubMed - as supplied by publisher]

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The glutathione-related detoxication responses to juvenile and ecdysone hormones in Galleria mellonella.

The glutathione-related detoxication responses to juvenile and ecdysone hormones in Galleria mellonella.

Comp Biochem Physiol C Toxicol Pharmacol. 2013 May 14;

Authors: Tarhan L, Kayal? HA, Karacali S, Y?k?lmaz S

PMID: 23684736 [PubMed - as supplied by publisher]

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Mortality rate increases steeply with nonadherence to statin therapy in patients with acute coronary syndrome.

Mortality rate increases steeply with nonadherence to statin therapy in patients with acute coronary syndrome.

Clin Cardiol. 2012 Nov;35(11):E22-7

Authors: Allonen J, Nieminen MS, Lokki M, Parkkonen O, Vaara S, Perola M, Hiekkalinna T, Strandberg TE, Sinisalo J

Abstract
BACKGROUND: In a prospective cohort of consecutive acute coronary syndrome (ACS) patients, we compared the adherence rate of statin usage and mortality rate during a median follow-up of 23 months.
HYPOTHESIS: Adherence to statin therapy after acute coronary syndrome affects mortality rate.
METHODS: We analyzed ACS patients (N = 1969; age, 65.9 � 11.8 years; female 30.4%) who underwent angiography between March 2006 and March 2008. The postdischarge usage of statins was based on the purchase register of the Social Insurance Institution of Finland. The death rate was verified from Statistics Finland.
RESULTS: At discharge, the rate of statin prescription to patients was 95.4% (n = 1878). When comparing adherent patients (n = 1200; 61.7%), who purchased the medication systematically until the end of the median 23-month follow-up, with nonadherent patients (n = 94; 4.8%), who did not use the medication at all, there was a vast difference in absolute death rate between the groups: 4.9% vs 14.9%, respectively (P < 0.001). We conducted Cox proportional hazards model with ACS type, cerebrovascular attack, diabetes, age, 3-artery disease, and cancer as adjusted confounders. Compared with regular statin users, nonusers were associated with a >2� increased hazard ratio of mortality (hazard ratio: 2.70, 95% confidence interval: 1.49-4.90, P = 0.001).
CONCLUSIONS: Statin medication is essential for discharged ACS patients. They should be strongly encouraged to purchase and use it.

PMID: 22961648 [PubMed - indexed for MEDLINE]

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2013年5月22日星期三

GSK-3? is a central regulator of age-related pathologies in mice.

GSK-3? is a central regulator of age-related pathologies in mice.

J Clin Invest. 2013 Apr 1;123(4):1821-32

Authors: Zhou J, Freeman TA, Ahmad F, Shang X, Mangano E, Gao E, Farber J, Wang Y, Ma XL, Woodgett J, Vagnozzi RJ, Lal H, Force T

Abstract
Aging is regulated by conserved signaling pathways. The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases regulates several of these pathways, but the role of GSK-3 in aging is unknown. Herein, we demonstrate premature death and acceleration of age-related pathologies in the Gsk3a global KO mouse. KO mice developed cardiac hypertrophy and contractile dysfunction as well as sarcomere disruption and striking sarcopenia in cardiac and skeletal muscle, a classical finding in aging. We also observed severe vacuolar degeneration of myofibers and large tubular aggregates in skeletal muscle, consistent with impaired clearance of insoluble cellular debris. Other organ systems, including gut, liver, and the skeletal system, also demonstrated age-related pathologies. Mechanistically, we found marked activation of mTORC1 and associated suppression of autophagy markers in KO mice. Loss of GSK-3?, either by pharmacologic inhibition or Gsk3a gene deletion, suppressed autophagy in fibroblasts. mTOR inhibition rescued this effect and reversed the established pathologies in the striated muscle of the KO mouse. Thus, GSK-3? is a critical regulator of mTORC1, autophagy, and aging. In its absence, aging/senescence is accelerated in multiple tissues. Strategies to maintain GSK-3? activity and/or inhibit mTOR in the elderly could retard the appearance of age-related pathologies.

PMID: 23549082 [PubMed - indexed for MEDLINE]

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Six-month IVUS and two-year clinical outcomes in the EVOLVE FHU trial: a randomised evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting stent.

Six-month IVUS and two-year clinical outcomes in the EVOLVE FHU trial: a randomised evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting stent.

EuroIntervention. 2013 May 22;

Authors: Meredith IT, Verheye S, Weissman NJ, Barragan P, Scott D, Ch�varri V, West NE, Kelb�k H, Whitbourn R, Walters DI, Kubica J, Thuesen L, Masotti M, Banning A, Sj�gren I, Stables RH, Allocco DJ, Dawkins KD

Abstract
Aims: The EVOLVE FHU trial demonstrated non-inferiority of six-month late loss with two dose formulations of SYNERGY, a novel bioabsorbable polymer everolimus-eluting stent (EES) compared with the durable polymer PROMUS Element (PE) EES. The current analysis describes the six-month IVUS and clinical results through two years from the EVOLVE FHU trial. Methods and results: EVOLVE recruited 291 patients from 29 centres. At six months, IVUS-assessed in-stent net volume obstruction was 3.40�5.06% for PROMUS Element (PE) vs. 2.68�4.60% for SYNERGY (p=0.34) and 3.09�4.29% for SYNERGY � dose (p=0.68 vs. PE). There were no significant differences between groups for any other measured IVUS parameter including resolved, persistent, and late-acquired incomplete stent apposition (ISA). At two years, target lesion failure (TLF) was 6.1% for PE vs. 5.5% for SYNERGY (p=0.87) and 5.2% for SYNERGY � dose (p=0.81). There were no significant differences between groups for cardiac death, repeat revascularisation, MI or stent thrombosis through two years. Conclusions: At six months, everolimus delivered from an ultrathin bioabsorbable abluminal polymer resulted in equivalent net volume obstruction and ISA compared with a permanent polymer EES. There were no significant differences between PE and either SYNERGY stent for any major cardiac endpoint through two years. Clinical trials number: NCT01135225.

PMID: 23688934 [PubMed - as supplied by publisher]

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TNF-alpha and LPA promote synergistic expression of COX-2 in human colonic myofibroblasts: role of LPA-mediated transactivation of upregulated EGFR.

TNF-alpha and LPA promote synergistic expression of COX-2 in human colonic myofibroblasts: role of LPA-mediated transactivation of upregulated EGFR.

BMC Gastroenterol. 2013 May 20;13(1):90

Authors: Yoo J, Perez CE, Nie W, Sinnett-Smith J, Rozengurt E

Abstract
BACKGROUND: Enhanced EGF receptor (EGFR) signaling is a hallmark of many human cancers, though the role of enhanced EGFR signaling within the surrounding tumor stroma has not been well studied. The myofibroblast is an important stromal cell that demonstrates enhanced EGFR expression in the setting of inflammation, though the functional relevance is not known. We recently reported that TNF-alpha and the G protein-coupled receptor (GPCR) agonist lysophosphatidic acid (LPA) lead to synergistic cyclo-oxygenase-2 (COX-2) expression, an enzyme strongly associated with the development of colitis-associated cancer. Here, we investigate whether EGFR signaling plays a role in the synergistic COX-2 expression induced by LPA and TNF-alpha. METHODS: 18Co cells, a model of human colonic myofibroblasts, were grown to confluence on 35 x 10mm cell culture dishes and were used from passages 10--14. 18Co cells were treated with TNF-alpha (8.3 ng/ml) and LPA (10 muM). EGFR and COX-2 protein expression, Y1068 phosphorylation, and p42/44 MAPK phosphorylation were assessed by Western Blot, in the presence and absence of various inhibitors. RESULTS: Exposure of 18Co cells to either TNF-alpha or LPA alone had no effect on EGFR autophosphorylation at Y1068. However, chronic exposure to TNF-alpha led to upregulation of EGFR in association with sustained LPA-mediated EGFR phosphorylation at Y1068. TNF-alpha and LPA also led to sustained p42/44 MAPK phosphorylation and synergistic COX-2 expression, effects that were partially inhibited by the EGFR tyrosine kinase inhibitor AG1478. p42/44 MAPK phosphorylation and COX-2 expression were inhibited to the same degree by the MMP inhibitors GM6001 and BB-94, suggesting that LPA-mediated EGFR transactivation involved MMP-mediated release of EGFR ligands from the cell surface. The Src inhibitor SU6556 inhibited TNF-alpha/LPA-mediated EGFR phosphorylation at Y1068, p42/44 MAPK phosphorylation, and COX-2 expression in a dose-dependent fashion, suggesting an upstream role of Src in the transactivation of EGFR. CONCLUSION: Synergistic COX-2 expression induced by TNF-alpha and LPA involves Src/MMP-mediated transactivation of EGFR and downstream p42/44 MAPK activation in human colonic myofibroblasts. Enhanced EGFR expression induced by TNF-alpha promotes GPCR-mediated EGFR transactivation in colonic myofibroblasts, providing an important mechanism for stromal COX-2 over-expression that may predispose to the development of colitis-associated cancer.

PMID: 23688423 [PubMed - as supplied by publisher]

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DNA damage and transcriptional changes induced by tributyltin (TBT) after short in vivo exposures of Chironomus riparius (Diptera) larvae.

DNA damage and transcriptional changes induced by tributyltin (TBT) after short in vivo exposures of Chironomus riparius (Diptera) larvae.

Comp Biochem Physiol C Toxicol Pharmacol. 2013 May 14;

Authors: Morales M, Mart�nez-Paz P, Oz�ez I, Mart�nez-Guitarte JL, Morcillo G

PMID: 23684738 [PubMed - as supplied by publisher]

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DNA damage and transcriptional changes induced by tributyltin (TBT) after short in vivo exposures of Chironomus riparius (Diptera) larvae.

DNA damage and transcriptional changes induced by tributyltin (TBT) after short in vivo exposures of Chironomus riparius (Diptera) larvae.

Comp Biochem Physiol C Toxicol Pharmacol. 2013 May 14;

Authors: Morales M, Mart�nez-Paz P, Oz�ez I, Mart�nez-Guitarte JL, Morcillo G

PMID: 23684738 [PubMed - as supplied by publisher]

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2013年5月21日星期二

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

PMID: 22612069 [PubMed - indexed for MEDLINE]

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Tivantinib in hepatocellular carcinoma.

Tivantinib in hepatocellular carcinoma.

Expert Opin Investig Drugs. 2013 Jan;22(1):141-7

Authors: Trojan J, Zeuzem S

Abstract
INTRODUCTION: Tivantinib (ARQ 197) is a selective, oral MET receptor tyrosine kinase inhibitor with broad-spectrum antitumor activity as single agent and in combination in preclinical studies including several MET overexpressing cell lines. AREAS COVERED: This paper covers the preclinical data, the Phase I studies as monotherapy or in combination with sorafenib, and a Phase II study as second-line systemic treatment in patients with advanced hepatocellular carcinoma (HCC). The analysis of MET expression as companion diagnostic and the safety profile of tivantinib in HCC are discussed. EXPERT OPINION: Tivantinib, a novel MET inhibitor with an ATP-independent binding mechanism, stabilizes the inactive conformation of the MET receptor tyrosine kinase, thus disrupting constitutive and ligand-mediated activation. MET overexpression was shown as a negative prognostic factor in HCC after sorafenib failure. Tivantinib demonstrated a nearly doubling of progression free and overall survival in the MET high group compared to placebo in a Phase II study in patients with advanced HCC as second-line treatment. The activity of tivantinib in combination with sorafenib is also promising. Adverse events include hematological toxicity, asthenia and loss of appetite. The initially high incidence of neutropenia in patients with HCC lead to dose reduction from 360 mg b.i.d. to 240 mg b.i.d. Currently, a pivotal Phase III study in advanced, MET-high HCC after sorafenib failure is planned.

PMID: 23167786 [PubMed - indexed for MEDLINE]

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Biodegradable Polymer Biolimus-eluting Stent versus Durable Polymer Everolimus-eluting Stent: a randomized, controlled, non-inferiority trial.

Biodegradable Polymer Biolimus-eluting Stent versus Durable Polymer Everolimus-eluting Stent: a randomized, controlled, non-inferiority trial.

J Am Coll Cardiol. 2013 May 15;

Authors: Natsuaki M, Kozuma K, Morimoto T, Kadota K, Muramatsu T, Nakagawa Y, Akasaka T, Igarashi K, Tanabe K, Morino Y, Ishikawa T, Nishikawa H, Awata M, Abe M, Okada H, Takatsu Y, Ogata N, Kimura K, Urasawa K, Tarutani Y, Shiode N, Kimura T

Abstract
OBJECTIVES: The NOBORI(TM) Biolimus-Eluting versus XIENCE(TM)/PROMUS(TM) Everolimus-eluting stent Trial (NEXT) was designed for evaluating non-inferiority of biolimus-eluting stent (BES) relative to everolimus-eluting stent (EES) in terms of target-lesion revascularization (TLR) at 1-year. BACKGROUND: Efficacy and safety data comparing biodegradable polymer BES with durable polymer cobalt-chromium EES are currently limited. METHODS: NEXT trial is a prospective, multicenter, randomized, open label, non-inferiority trial comparing BES with EES. RESULTS: Between May and October 2011, 3235 patients were randomly assigned to receive either BES (1617 patients) or EES (1618 patients). At 1-year, the primary efficacy endpoint of TLR occurred in 67 patients (4.2%) in the BES group, and in 66 patients (4.2%) in the EES group, demonstrating non-inferiority of BES relative to EES (P non-inferiority<0.0001, and P superiority=0.93). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.25% versus 0.06%, P=0.18). Angiographic sub-study enrolling 528 patients (BES: 263 patients, and EES: 265 patients) demonstrated non-inferiority of BES relative to EES regarding the primary angiographic endpoint of in-segment late loss (0.03�0.39mm versus 0.06�0.45mm, P non-inferiority<0.0001, and P superiority=0.52) at 266�43 days after stent implantation. CONCLUSIONS: One-year clinical and angiographic outcome after BES implantation was non-inferior to and not different from that after EES implantation in a mostly stable coronary artery disease population. One-year clinical outcome after both BES- and EES-use was excellent with low rate of TLR and extremely low rate of stent thrombosis. CLINICAL TRIAL IDENTIFIER: NCT01303640.

PMID: 23684673 [PubMed - as supplied by publisher]

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A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae.

BMC Genomics. 2013 May 10;14(1):317

Authors: Dermauw W, Osborne EJ, Clark RM, Grbi M, Tirry L, Van Leeuwen T

Abstract
BACKGROUND: The ABC (ATP-binding cassette) gene superfamily is widespread across all living species. The majority of ABC genes encode ABC transporters, which are membrane-spanning proteins capable of transferring substrates across biological membranes by hydrolyzing ATP. Although ABC transporters have often been associated with resistance to drugs and toxic compounds, within the Arthropoda ABC gene families have only been characterized in detail in several insects and a crustacean. In this study, we report a genome-wide survey and expression analysis of the ABC gene superfamily in the spider mite, Tetranychus urticae, a chelicerate ~ 450 million years diverged from other Arthropod lineages. T. urticae is a major agricultural pest, and is among of the most polyphagous arthropod herbivores known. The species resists a staggering array of toxic plant secondary metabolites, and has developed resistance to all major classes of pesticides in use for its control. RESULTS: We identified 103 ABC genes in the T. urticae genome, the highest number discovered in a metazoan species to date. Within the T. urticae ABC gene set, all members of the eight currently described subfamilies (A to H) were detected. A phylogenetic analysis revealed that the high number of ABC genes in T. urticae is due primarily to lineage-specific expansions of ABC genes within the ABCC, ABCG and ABCH subfamilies. In particular, the ABCC subfamily harbors the highest number of T. urticae ABC genes (39). In a comparative genomic analysis, we found clear orthologous relationships between a subset of T. urticae ABC proteins and ABC proteins in both vertebrates and invertebrates known to be involved in fundamental cellular processes. These included members of the ABCB-half transporters, and the ABCD, ABCE and ABCF families. Furthermore, one-to-one orthologues could be distinguished between T. urticae proteins and human ABCC10, ABCG5 and ABCG8, the Drosophila melanogaster sulfonylurea receptor and ecdysone-regulated transporter E23. Finally, expression profiling revealed that ABC genes in the ABCC, ABCG ABCH subfamilies were differentially expressed in multi-pesticide resistant mite strains and in mites transferred to challenging (toxic) host plants. CONCLUSIONS: In this study we present the first comprehensive analysis of ABC genes in a polyphagous arthropod herbivore. We demonstrate that the broad plant host range and high levels of pesticide resistance in T. urticae are associated with lineage-specific expansions of ABC genes, many of which respond transcriptionally to xenobiotic exposure. This ABC catalogue will serve as a basis for future biochemical and toxicological studies. Obtaining functional evidence that these ABC subfamilies contribute to xenobiotic tolerance should be the priority of future research.

PMID: 23663308 [PubMed - as supplied by publisher]

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2013年5月20日星期一

Differential prognostic effect of intravascular ultrasound use according to implanted stent length.

Differential prognostic effect of intravascular ultrasound use according to implanted stent length.

Am J Cardiol. 2013 Mar 15;111(6):829-35

Authors: Ahn JM, Han S, Park YK, Lee WS, Jang JY, Kwon CH, Park GM, Cho YR, Lee JY, Kim WJ, Park DW, Kang SJ, Lee SW, Kim YH, Lee CW, Kim JJ, Park SW, Park SJ

Abstract
It is unknown whether the use of intravascular ultrasound (IVUS) guidance during percutaneous coronary intervention can attenuate the stent length effect on clinical outcomes. The aim of the present study was to determine the differential prognostic effect of IVUS according to the implanted stent length. We enrolled 3,244 consecutive patients from the Interventional Cardiology Research In-cooperation Society-Drug-Eluting Stents (IRIS-DES) registry who had undergone single or overlapping stent implantation. The primary end point was major adverse cardiac events (MACE; a composite of death, myocardial infarction, and target vessel revascularization). The study population was divided by the tertiles of implanted stent length and IVUS usage. IVUS use was at the discretion of the operator. After adjusting for significant covariates, the stent length was significantly associated with the risk of MACE in the no-IVUS group (hazard ratio 1.13, 95% confidence interval 1.01 to 1.28, p = 0.042) but not in the IVUS group (hazard ratio 1.08, 95% confidence interval 0.97 to 1.20, p = 0.16). In addition, in patients with an implanted stent length of ?22 mm (n = 998), the risk of MACE was not significantly different between the IVUS group and the no-IVUS group (hazard ratio 1.06, 95% confidence interval 0.50 to 2.28, p = 0.88). In contrast, in patients with a longer implanted stent length, the risk of MACE was significantly lower in the IVUS group than in the no-IVUS group (hazard ratio 0.47, 95% confidence interval 0.24 to 0.92, p = 0.027 for 23 to 32 mm, n = 1,109; hazard ratio 0.57, 95% confidence interval 0.33 to 0.98, p = 0.042 for ?33 mm, n = 1,137). In conclusion, IVUS usage can attenuate the detrimental effect of the increase in the implanted stent length, supporting IVUS usage, particularly during percutaneous coronary intervention with long stent implantation.

PMID: 23273529 [PubMed - indexed for MEDLINE]

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Effects of celecoxib treatment over the AKT pathway in head and neck squamous cell carcinoma.

Effects of celecoxib treatment over the AKT pathway in head and neck squamous cell carcinoma.

J Oral Pathol Med. 2013 May 16;

Authors: Abrah�o AC, Giudice FS, Sperandio FF, Pinto Junior DD

Abstract
BACKGROUND: Celecoxib, a non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2 (COX-2), has shown an important anticarcinogenic effect for the treatment of squamous cell carcinoma. The use of COX-2 inhibitors has effectively inhibited the growth of Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines, while a recent phase 1 trial demonstrated good response rate of cancer cells to this drug with minimal toxicity. Possible targets of celecoxib include proteins involved in cell proliferation and apoptosis control. Additionally, celecoxib antitumoral activity has been linked with a COX-2-independent event. METHODS: To better understand which cellular mechanisms are targeted by celecoxib, its effects upon the Akt signaling pathway using two different HNSCC cell lines were analyzed through cell viability assay, immunofluorescence, and Western blotting. RESULTS: The results showed decreased levels of Cyclin D1 and pAkt protein expression in vitro. The number of viable cells was also diminished after celecoxib treatment. CONCLUSION: As Akt pathway seems to be a valuable target for the HNSCC therapy, the results presented herein confirm that celecoxib can be considered as an alternative adjuvant drug for HNSCC treatment.

PMID: 23679684 [PubMed - as supplied by publisher]

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Plum, an Immunoglobulin Superfamily Protein, Regulates Axon Pruning by Facilitating TGF-? Signaling.

Plum, an Immunoglobulin Superfamily Protein, Regulates Axon Pruning by Facilitating TGF-? Signaling.

Neuron. 2013 May 8;78(3):456-68

Authors: Yu XM, Gutman I, Mosca TJ, Iram T, Ozkan E, Garcia KC, Luo L, Schuldiner O

Abstract
Axon pruning during development is essential for proper wiring of the mature nervous system, but its�regulation remains poorly understood. We have identified an immunoglobulin superfamily (IgSF) transmembrane protein, Plum, that is cell autonomously required for axon pruning of mushroom body (MB) ? neurons and for ectopic synapse refinement at the developing neuromuscular junction in�Drosophila. Plum promotes MB ? neuron axon pruning by regulating the expression of Ecdysone Receptor-B1, a key initiator of axon pruning. Genetic analyses indicate that Plum acts to facilitate signaling of Myoglianin, a glial-derived TGF-?, on MB ? neurons upstream of the type-I TGF-? receptor Baboon. Myoglianin, Baboon, and Ecdysone Receptor-B1 are also required for neuromuscular junction ectopic synapse refinement. Our study highlights both IgSF proteins and TGF-? facilitation as key promoters of developmental axon elimination and demonstrates a mechanistic conservation between MB axon pruning during metamorphosis and the refinement of ectopic larval neuromuscular connections.

PMID: 23664613 [PubMed - in process]

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JJK694, a synthesized obovatol derivative, inhibits platelet activation by suppressing cyclooxygenase and lipoxygenase activities.

JJK694, a synthesized obovatol derivative, inhibits platelet activation by suppressing cyclooxygenase and lipoxygenase activities.

Biosci Biotechnol Biochem. 2012;76(11):2038-43

Authors: Yu JY, Lee JJ, Jung JK, Min YK, Kim TJ, Ma JY, Lee MY, Yun YP

Abstract
Obovatol has various biological activities, including anti-proliferative, neurotrophic, anti-fibrillogenic, anti-platelet, anti-fungal and anti-inflammatory activities. In this study, we investigated the effects of JJK694, a synthesized obovatol derivative, on rabbit platelet activation and its molecular mechanisms. JJK694 significantly inhibited washed rabbit platelet aggregation and serotonin secretion induced by collagen and arachidonic acid, but had little effect on thrombin- or U46619-induced aggregation. These results suggest that JJK694 selectively inhibits collagen- and arachidonic acid-mediated signaling. JJK694 also showed a concentration-dependent decrease in cytosolic Ca(2+) mobilization, but it had no effect on arachidonic acid liberation. On the other hand, it significantly inhibited the formation of arachidonic acid metabolites, including thromboxane A(2) (TXA(2)), prostaglandin D(2), and 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), by suppression of cyclooxygenase (COX)-1 and lipoxygenase (LOX) activities. These results indicate that JJK694 hasanti-platelet activities through inhibition of arachidonic acid metabolite production by suppression of COX-1 and LOX activities.

PMID: 23132562 [PubMed - indexed for MEDLINE]

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ATF4 and IRE1? inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock.

ATF4 and IRE1? inhibit DNA repair protein DNA-dependent protein kinase 1 induced by heat shock.

Mol Cell Biochem. 2012 Dec;371(1-2):225-32

Authors: Zhu H, Guo FJ, Zhao W, Zhou J, Liu Y, Song F, Wang Y

Abstract
With the increase of environment temperature, more and more attentions are payed to the effects of heat stress. Cells under heat shock either are adapted to the condition or are damaged and dead. In this paper, we found that heat shock induced endoplasmic reticulum (ER) stress. ATF4, PERK, and IRE1? were induced by heat shock of 45 �C in the transcriptional level. Under the stress of 45 �C, PERK was phosphorylated and XBP1s was detected. The result indicated that heat shock could induce the ER stress. We found that heat shock of 45 �C induced the dysregulation of HSP70 and DNA-PKcs, and downregulated the expression of PARP1 and XRCC1. Further results showed that after the knockdown of ATF4 or IRE1?, the expression of DNA-PKcs and XRCC1 were increased. It was indicated that ATF4 and IRE1? could inhibit the expression of DNA-PKcs and XRCC1 under the heat stress. Our results suggested that heat shock could activate ER stress. IRE1? and ATF4, as the important ER stress molecules, could inhibit the expression of DNA repair proteins DNA-PKcs, XRCC1, and HSP70 under heat shock. Downregulation of DNA repair proteins could aggravate the cell damage that may cause cell apoptosis. This may explain that heat shock could increase the lethality of chemotherapeutic drugs on tumor cells.

PMID: 23001845 [PubMed - indexed for MEDLINE]

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2013年5月19日星期日

Effects of celecoxib treatment over the AKT pathway in head and neck squamous cell carcinoma.

Effects of celecoxib treatment over the AKT pathway in head and neck squamous cell carcinoma.

J Oral Pathol Med. 2013 May 16;

Authors: Abrah�o AC, Giudice FS, Sperandio FF, Pinto Junior DD

PMID: 23679684 [PubMed - as supplied by publisher]

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NSAIDs and fracture healing.

NSAIDs and fracture healing.

Curr Opin Rheumatol. 2013 May 15;

Authors: Geusens P, Emans PJ, de Jong JJ, van den Bergh J

Abstract
PURPOSE OF REVIEW: Published data raise concerns about the use of nonselective NSAIDs and selective cyclo-oxygenase (COX)-2 inhibitors as anti-inflammatory or analgesic drugs in patients after a recent fracture or who are undergoing (uncemented) arthroplasty or osteotomy. However, clinical reports on the effect of COX-2 inhibition on fracture healing in humans have been variable and inconclusive. This review gives an overview of the published data and an advice when to avoid NSAIDs. RECENT FINDINGS: Prostaglandins play an important role as mediators of inflammation and COX are required for their production. Inflammation is an essential step in the fracture healing process in which prostaglandin production by COX-2 is involved. Data from animal studies suggest that NSAIDs, which inhibit COX-2, can impair fracture healing due to the inhibition of the endochondral ossification pathway. Animal data suggest that the effects of COX-2 inhibitors are dependent on the timing, duration, and dose, and that these effects are reversible. SUMMARY: These animal data, together with the view of limited scientifically robust clinical evidence in humans, indicate that physicians consider only short-term administration of COX-2 inhibitors or other drugs in the pain management of patients who are in the phase of fracture or other bone defect healing. COX-2-inhibitors should be considered a potential risk factor for fracture healing, and therefore to be avoided in patients at risk for delayed fracture healing.

PMID: 23680778 [PubMed - as supplied by publisher]

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Plum, an Immunoglobulin Superfamily Protein, Regulates Axon Pruning by Facilitating TGF-? Signaling.

Plum, an Immunoglobulin Superfamily Protein, Regulates Axon Pruning by Facilitating TGF-? Signaling.

Neuron. 2013 May 8;78(3):456-68

Authors: Yu XM, Gutman I, Mosca TJ, Iram T, Ozkan E, Garcia KC, Luo L, Schuldiner O

PMID: 23664613 [PubMed - in process]

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Tivantinib in hepatocellular carcinoma.

Tivantinib in hepatocellular carcinoma.

Expert Opin Investig Drugs. 2013 Jan;22(1):141-7

Authors: Trojan J, Zeuzem S

PMID: 23167786 [PubMed - indexed for MEDLINE]

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