Применение оксидно-рутениевых титановых анодов, модифицированных сурьмой для очистки воды

Rationale: Unlike conventional dendritic cells, plasmacytoid DCs (PDC) are poor in antigen presentation and critical for type 1 interferon response. Though proposed to be present in human atherosclerotic lesions, their role in atherosclerosis remains elusive. Objective: To investigate the role of PDC in atherosclerosis. Methods and Results: We show that PDC are scarcely present in human atherosclerotic lesions and almost absent in mouse plaques. Surprisingly, PDC depletion by 120G8 mAb administration was seen to promote plaque T-cell accumulation and exacerbate lesion development and progression in LDLr(-/-) mice. PDC depletion was accompanied by increased CD4(+) T-cell proliferation, interferon-gamma expression by splenic T cells, and plasma interferon-gamma levels. Lymphoid tissue PDC from atherosclerotic mice showed increased indoleamine 2,3-dioxygenase (IDO) expression and IDO blockage abrogated the PDC suppressive effect on T-cell proliferation. Conclusions: Our data reveal a protective role for PDC in atherosclerosis, possibly by dampening T-cell proliferation and activity in peripheral lymphoid tissue, rendering PDC an interesting target for future therapeutic interventions. (Circ Res. 2011;109:1387-1395.

Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function

Objective-Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) mediates inflammatory and potentially proatherogenic effects, whereas the role of intracellular NAMPT (iNAMPT), the rate limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD)+ generation, in atherogenesis is largely unknown. Here we investigated the effects of iNAMPT overexpression in leukocytes on inflammation and atherosclerosis. Approach and Results-Low-density lipoprotein receptor-deficient mice with hematopoietic overexpression of human iNAMPT (iNAMPThi), on a western type diet, showed attenuated plaque burden with features of lesion stabilization. This anti-atherogenic effect was caused by improved resistance of macrophages to apoptosis by attenuated chemokine (C-C motif) receptor 2-dependent monocyte chemotaxis and by skewing macrophage polarization toward an anti-inflammatory M2 phenotype. The iNAMPThi phenotype was almost fully reversed by treatment with the NAMPT inhibitor FK866, indicating that iNAMPT catalytic activity is instrumental in the atheroprotection. Importantly, iNAMPT overexpression did not induce any increase in eNAMPT, and eNAMPT had no effect on chemokine (C-C motif) receptor 2 expression and promoted an inflammatory M1 phenotype in macrophages. The iNAMPT-mediated effects at least partly involved sirtuin 1-dependent molecular crosstalk of NAMPT and peroxisome proliferator-activated receptor γ. Finally, iNAMPT and peroxisome proliferator-activated receptor γ showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor γ pathway also in human carotid atherosclerosis. Conclusions-This study highlights the functional dichotomy of intracellular versus extracellular NAMPT, and unveils a critical role for the iNAMPT-peroxisome proliferator-activated receptor γ axis in atherosclerosis.Netherlands Heart Foundation 2003T201European Union FP7–PEOPLE–2007–2–1–IEF, FP7– PEOPLE–2010–RGMinisterio de Economía y Competitividad AGL2011–2900

Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPAR gamma-Dependent Monocyte Differentiation and Function

Objective-Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) mediates inflammatory and potentially proatherogenic effects, whereas the role of intracellular NAMPT (iNAMPT), the rate limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD)(+) generation, in atherogenesis is largely unknown. Here we investigated the effects of iNAMPT overexpression in leukocytes on inflammation and atherosclerosis. Approach and Results-Low-density lipoprotein receptor-deficient mice with hematopoietic overexpression of human iNAMPT (iNAMPT(hi)), on a western type diet, showed attenuated plaque burden with features of lesion stabilization. This anti-atherogenic effect was caused by improved resistance of macrophages to apoptosis by attenuated chemokine (C-C motif) receptor 2-dependent monocyte chemotaxis and by skewing macrophage polarization toward an anti-inflammatory M2 phenotype. The iNAMPT(hi) phenotype was almost fully reversed by treatment with the NAMPT inhibitor FK866, indicating that iNAMPT catalytic activity is instrumental in the atheroprotection. Importantly, iNAMPT overexpression did not induce any increase in eNAMPT, and eNAMPT had no effect on chemokine (C-C motif) receptor 2 expression and promoted an inflammatory M1 phenotype in macrophages. The iNAMPT-mediated effects at least partly involved sirtuin 1-dependent molecular crosstalk of NAMPT and peroxisome proliferator-activated receptor.. Finally, iNAMPT and peroxisome proliferator-activated receptor. showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor. pathway also in human carotid atherosclerosis. Conclusions-This study highlights the functional dichotomy of intracellular versus extracellular NAMPT, and unveils a critical role for the iNAMPT-peroxisome proliferator-activated receptor. axis in atherosclerosis

Endothelial ADAM10 controls cellular response to oxLDL and its deficiency exacerbates atherosclerosis with intraplaque hemorrhage and neovascularization in mice

IntroductionThe transmembrane protease A Disintegrin And Metalloproteinase 10 (ADAM10) displays a “pattern regulatory function,” by cleaving a range of membrane-bound proteins. In endothelium, it regulates barrier function, leukocyte recruitment and angiogenesis. Previously, we showed that ADAM10 is expressed in human atherosclerotic plaques and associated with neovascularization. In this study, we aimed to determine the causal relevance of endothelial ADAM10 in murine atherosclerosis development in vivo.Methods and resultsEndothelial Adam10 deficiency (Adam10ecko) in Western-type diet (WTD) fed mice rendered atherogenic by adeno-associated virus-mediated PCSK9 overexpression showed markedly increased atherosclerotic lesion formation. Additionally, Adam10 deficiency was associated with an increased necrotic core and concomitant reduction in plaque macrophage content. Strikingly, while intraplaque hemorrhage and neovascularization are rarely observed in aortic roots of atherosclerotic mice after 12 weeks of WTD feeding, a majority of plaques in both brachiocephalic artery and aortic root of Adam10ecko mice contained these features, suggestive of major plaque destabilization. In vitro, ADAM10 knockdown in human coronary artery endothelial cells (HCAECs) blunted the shedding of lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) and increased endothelial inflammatory responses to oxLDL as witnessed by upregulated ICAM-1, VCAM-1, CCL5, and CXCL1 expression (which was diminished when LOX-1 was silenced) as well as activation of pro-inflammatory signaling pathways. LOX-1 shedding appeared also reduced in vivo, as soluble LOX-1 levels in plasma of Adam10ecko mice was significantly reduced compared to wildtypes.DiscussionCollectively, these results demonstrate that endothelial ADAM10 is atheroprotective, most likely by limiting oxLDL-induced inflammation besides its known role in pathological neovascularization. Our findings create novel opportunities to develop therapeutics targeting atherosclerotic plaque progression and stability, but at the same time warrant caution when considering to use ADAM10 inhibitors for therapy in other diseases

Low- but not high-dose FK506 treatment confers atheroprotection due to alternative macrophage activation and unaffected cholesterol levels

Previous studies showed both pro- and anti-atherogenic effects of immunosuppressant drug FK506 on atherosclerosis. As these divergent/paradoxical results of FK506 may at least in part be attributable to differences in FK506 dosing, we have, in the current study, assessed dose-dependent effects of FK506 on atherosclerotic lesion formation as well as on inflammatory parameters relevant to atherosclerosis. Unlike low-dose FK506, high-dose FK506 did not protect against atherosclerosis in ApoE-/- mice. The high-dose induced hypercholesterolaemia, whereas the low-dose did not. Both low- and high-dose FK506 treatment significantly reduced systemic CD3+ and CD4+CD25+ T-cell populations, and showed similar suppression of FoxP3 regulatory T-cell populations. Increased IL-4+ CD4+ T-cells and decreased IgG-MDA-LDL antibody titres pointed to a selective, albeit modest Th2 skewing in the high-dose treatment group, despite the advanced stage of atherosclerosis. Low concentrations of FK506, however, skewed bone marrow-derived macrophage polarisation towards a M2 macrophage phenotype, whereas high concentration did not. A low-dose FK506 treatment regime protected against atherosclerosis by suppressing T-cell activation and favouring (M2) macrophage polarisation. Although a high-dose FK506 treatment effected a similar T-cell suppressive effect, with an even more pronounced shift towards Th2 type immune responses, this did not translate in atheroprotection due to the hypercholesterolaemia and absent M2 skewin

The Antiviral Agent Cidofovir Induces DNA Damage and Mitotic Catastrophe in HPV-Positive and -Negative Head and Neck Squamous Cell Carcinomas In Vitro

Cidofovir (CDV) is an antiviral agent with antiproliferative properties. The aim of our study was to investigate the efficacy of CDV in HPV-positive and -negative head and neck squamous cell carcinoma (HNSCC) cell lines and whether it is caused by a difference in response to DNA damage. Upon CDV treatment of HNSCC and normal oral keratinocyte cell lines, we carried out MTT analysis (cell viability), flow cytometry (cell cycle analysis), (immuno) fluorescence and western blotting (DNA double strand breaks, DNA damage response, apoptosis and mitotic catastrophe). The growth of the cell lines was inhibited by CDV treatment and resulted in gamma-H2AX accumulation and upregulation of DNA repair proteins. CDV did not activate apoptosis but induced S- and G2/M phase arrest. Phospho-Aurora Kinase immunostaining showed a decrease in the amount of mitoses but an increase in aberrant mitoses suggesting mitotic catastrophe. In conclusion, CDV inhibits cell growth in HPV-positive and -negative HNSCC cell lines and was more profound in the HPV-positive cell lines. CDV treated cells show accumulation of DNA DSBs and DNA damage response activation, but apoptosis does not seem to occur. Rather our data indicate the occurrence of mitotic catastrophe.</p

HURUF AL JAR FI QISHAH ANA AL MAUT AL QASIRAH LI TAUFIQ AL HAKIM : DIRASAH TAHLILIYAH NAHWIYAH

Dalam tata bahasa Arab, kata (kalimat dalam bahasa Arab) sebagai satuan terkecil bahasa, sebagaimana dalam bahasa yang lain dapat dikelompokkan menjadi tiga macam; pertama isim, fi’il dan huruf. Yang kemudian dapat lebih mudah untuk dipelajari namun, penulis dalam hal ini hanya akan sedikit membahas bagian yang terakhir yang berkaitan dengan huruf khusunya huruf jer. Pembahasan dalam skripsi ini mengkaji tentang Huruf Jer dalam cerpen “Akulah Kematian” karya Taufiq Hakim, dengan pendekatan ilmu Nahwu. Masalah yang dikemukakan dalam rumusan masalah ini meliputi dua hal yaitu; huruf jer apa saja yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim dan apa saja makna huruf jer yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim. Dalam pembahasan skripsi ini peneliti menggunakan ilmu nahwu sebagai pisau analisis dan ilmu kebahasaan sebagai pendekatannya. Peneliti mengambil beberapa teori nahwu dari buku-buku yang mudah dimengerti dalam penjelasannya seperti kitab Jamiud Durus. Adapun tujuan pembahasan ini adalah untuk mengungkap ilmu kebahasan yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim, sedangkan metode penelitian yang dipakai adalah metode penelitian deskriptif kualitatif. Huruf Jer secara umum yang banyak dikemukakan oleh ahli nahwu berjumlah 20 huruf, sedangkan dalam cerpen “Akulah Kematian” karya Taufiq Hakim berjumlah 9 huruf yang terdiri dari (الباء، من، إلى، حتى، على، الكاف، عن، اللام، في) Adapun kesimpulan dalam penelitian ini bahwa di dalam cerpen “Akulah Kematian” terdapat 395 huruf jer, pertama: huruf jer berbentuk ba’ dengan makna ilshoq, mushohabah, as-sababiyyah wa at-ta’lil, at-ta’diyah, al-ist’la’, al-isti’anah, adz-dzhorfiyah, al-badal, al-‘iwadh. Harfu min dengan makna al-ibtida’ at-tab’iid, at-ta’kid, adz-dzorfiyah, dan makna ‘an. Harfu ila dengan makna al-intiha’, al-mushohabah, makna ‘inda. Huruf jer hatta dengan makna lil intiha’ ka ila. Huruf jer ‘an dengan makna almujawazah wal bu’du, makna min, dan makna ‘ala. Huruf jer ‘ala dengan makna al-isti’la’, makna min, makna ba’, makna ‘an, makna fi. Huruf jer fi dengan makna adz-dzorfiyah, al-muhohabah, al-isti’la’, dan makna ba. Huruf jer kaf dengan makna at-ta’lil, as-sababiyah, dan makna ‘ala. Huruf jer lam dengan makna al-isti’la’, al-milku, lamul-ikhtishah, as-sababiyah wat-ta’lil, sibhul-miku, dan taukid

Endothelial ADAM10 controls cellular response to oxLDL and its deficiency exacerbates atherosclerosis with intraplaque hemorrhage and neovascularization in mice.

INTRODUCTION The transmembrane protease A Disintegrin And Metalloproteinase 10 (ADAM10) displays a "pattern regulatory function," by cleaving a range of membrane-bound proteins. In endothelium, it regulates barrier function, leukocyte recruitment and angiogenesis. Previously, we showed that ADAM10 is expressed in human atherosclerotic plaques and associated with neovascularization. In this study, we aimed to determine the causal relevance of endothelial ADAM10 in murine atherosclerosis development in vivo. METHODS AND RESULTS Endothelial Adam10 deficiency (Adam10 ecko ) in Western-type diet (WTD) fed mice rendered atherogenic by adeno-associated virus-mediated PCSK9 overexpression showed markedly increased atherosclerotic lesion formation. Additionally, Adam10 deficiency was associated with an increased necrotic core and concomitant reduction in plaque macrophage content. Strikingly, while intraplaque hemorrhage and neovascularization are rarely observed in aortic roots of atherosclerotic mice after 12 weeks of WTD feeding, a majority of plaques in both brachiocephalic artery and aortic root of Adam10ecko mice contained these features, suggestive of major plaque destabilization. In vitro, ADAM10 knockdown in human coronary artery endothelial cells (HCAECs) blunted the shedding of lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) and increased endothelial inflammatory responses to oxLDL as witnessed by upregulated ICAM-1, VCAM-1, CCL5, and CXCL1 expression (which was diminished when LOX-1 was silenced) as well as activation of pro-inflammatory signaling pathways. LOX-1 shedding appeared also reduced in vivo, as soluble LOX-1 levels in plasma of Adam10ecko mice was significantly reduced compared to wildtypes. DISCUSSION Collectively, these results demonstrate that endothelial ADAM10 is atheroprotective, most likely by limiting oxLDL-induced inflammation besides its known role in pathological neovascularization. Our findings create novel opportunities to develop therapeutics targeting atherosclerotic plaque progression and stability, but at the same time warrant caution when considering to use ADAM10 inhibitors for therapy in other diseases.This work was supported by the Dutch Heart Foundation (Dr. E. Dekker grant 20120T79) and the Limburg University Fund (SWOL; Professor’s Fund) to MD, in part by DFG grant Lu869/8-1 to AL, the Cardiovascular Research Institute Maastricht (CARIM Ph.D.- award), the Alexander von Humboldt Foundation, a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University, the DZHK (German Centre for Cardiovascular Research) the BMBF (German Ministry of Education and Research), the NWO-ZonMw Veni (91619053), and the Fritz Thyssen Stiftung (Grant No. 10.20.2.043MN) to EV.S

Noninvasive diagnosis of ruptured peripheral atherosclerotic lesions and myocardial infarction by antibody profiling

Novel biomarkers, such as circulating (auto)antibody signatures, may improve early detection and treatment of ruptured atherosclerotic lesions and accompanying cardiovascular events, such as myocardial infarction. Using a phage-display library derived from cDNAs preferentially expressed in ruptured peripheral human atherosclerotic plaques, we performed serological antigen selection to isolate displayed cDNA products specifically interacting with antibodies in sera from patients with proven ruptured peripheral atherosclerotic lesions. Two cDNA products were subsequently evaluated on a validation series of patients with peripheral atherosclerotic lesions, healthy controls, and patients with coronary artery disease at different stages. Our biomarker set was able to discriminate between patients with peripheral ruptured lesions and patients with peripheral stable plaques with 100% specificity and 76% sensitivity. Furthermore, 93% of patients with an acute myocardial infarction (AMI) tested positive for our biomarkers, whereas all patients with stable angina pectoris tested negative. Moreover, 90% of AMI patients who initially tested negative for troponin T, for which a positive result is known to indicate myocardial infarction, tested positive for our biomarkers upon hospital admission. In conclusion, antibody profiling constitutes a promising approach for noninvasive diagnosis of atherosclerotic lesions, because a positive serum response against a set of 2 cDNA products showed a strong association with the presence of ruptured peripheral atherosclerotic lesions and myocardial infarction