bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymorphisms ofEDNRB,ATG, andACEgenes in salt-sensitive hypertensionThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Caprioli Jessica , Mele Caterina , Mossali Chiara , Gallizioli Laura , Giacchetti Gilberta , Noris Marina , Remuzzi Giuseppe , Benigni Ariela 
Published: August 2008

Almost 50% of hypertensive individuals manifest blood pressure changes in response to salt depletion or repletion and are termed “salt sensitive” (SS). Blunted activity of the endothelin (ET) system and the renin–angiotensin–aldosterone system (RAAS) have been reported as possible mechanisms contributing to salt sensitivity. Data are available that endothelin receptor subtype B (ETBR)-deficient rats develop salt-sensitive hypertension when fed a high-salt diet. Whether the ETBR gene (EDNRB) is involved in genetic predisposition to human salt-sensitive hypertension has not been studied so far. We screened EDNRB in 104 hypertensive patients (49 salt sensitive and 55 salt resistant) and 110 normotensive controls. No new sequence variation was found, but genotype distribution of the common polymorphism G1065A revealed that the AA + GA genotypes were significantly more frequent in salt-resistant than in salt-sensitive individuals (p = 0.007), suggesting a protective role for the A allele. We also screened angiotensinogen gene AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism ACE I/D and found an association between TT genotype and hypertension. A possible synergistic effect to salt-sensitive hypertension was found by combining EDNRB GG with ACE DD/ID genotypes. In conclusion, our data confirm the role of ET system and RAAS in salt-sensitive hypertension.
Inhalation of an endothelin receptor A antagonist attenuates pulmonary inflammation in experimental acute lung injuryThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Kalk Philipp , Senf Philine , Deja Maria , Petersen Bodil , Busch Thilo , Bauer Christian , Boemke Willehad , Kaisers Udo , Hocher Berthold 
Published: August 2008

We recently demonstrated that inhalation of the endothelin receptor A (ETA) antagonist LU 135252 improved arterial oxygenation and reduced pulmonary artery pressure in experimental acute lung injury (ALI). In this study we analyzed potential immune modulatory effects of inhaled LU 135252 in experimental ALI. ALI was induced by repeated lung lavage in intubated (100% O2) and anesthetized piglets. Animals were randomly assigned to inhale either nebulized LU 135252 (0.3 mg·kg–1, ALI + LU group, n = 8) or saline buffer (ALI control group, n = 16), both for 30 min. Surviving animals were sacrificed 6 h after induction of ALI, and lung tissue specimens were obtained from all animals for histology and immunhistochemistry. Induction of ALI significantly decreased arterial oxygenation in all animals. Inhalation of LU 135252 significantly reduced mortality and induced significant and sustained increase in Pao2 (316 ± 47 mm Hg vs. control 53 ± 3 mm Hg, p < 0.001). We measured a significant reduction in the number of pulmonary leukocyte L1 antigen-positive cells in ALI + LU animals (8% ± 1% positive cells vs. control 12% ± 2% positive cells, p < 0.05). The number of CD3-positive cells was not altered by treatment with LU 135252. Pulmonary tissue concentration of IL-6 was significantly suppressed by LU 135252 inhalation (4 ± 1 pg·100 mg–1 wet weight vs. control 7 ± 1 pg·100 mg–1 wet weight, p < 0.05). Concentrations of TNF-α, IL-1β, and ET-1 in pulmonary tissue were not influenced by inhalation of LU 135252. In conclusion, we demonstrated that inhalation of LU 135252 not only improves mortality and gas exchange, but also blunts the local immune response in experimental ALI.
Nonpeptidic antagonists of ETAand ETBreceptors reverse the ET-1-induced sustained increase of cytosolic and nuclear calcium in human aortic vascular smooth muscle cellsThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Bkaily Ghassan , Choufani Sanaa , Avedanian Levon , Ahmarani Lena , Nader Moni , Jacques Danielle , D’Orléans-Juste Pedro , Al Khoury Johny 
Published: August 2008

Our previous work showed that ET-1 induced a concentration-dependent increase of cytosolic Ca2+([Ca]c) and nuclear Ca2+([Ca]n) in human aortic vascular smooth muscle cells (hVSMCs). In the present study, using hVSMCs and 3-dimensional confocal microscopy coupled to the Ca2+fluorescent probe Fluo-3, we showed that peptidic antagonists of ETAand ETBreceptors (BQ-123 (10−6mol/L) and BQ-788 (10−7mol/L), respectively) prevented, but did not reverse, ET-1-induced sustained increase of [Ca]cand [Ca]n. In contrast, nonpeptidic antagonists of ETAand ETB(respectively, BMS-182874 (10−8–10−6mol/L) and A-192621 (10−7mol/L)) both prevented and reversed ET-1-induced sustained increase of [Ca]cand [Ca]n. Furthermore, activation of the ETBreceptor alone using the specific agonist IRL-1620 (10−9mol/L) induced sustained increases of [Ca]cand [Ca]n, and subsequent administration of ET-1 (10−7mol/L) further increased nuclear Ca2+. ET-1-induced increase of [Ca]cand [Ca]nwas completely blocked by extracellular application of the Ca2+chelator EGTA. Pretreatment with the G protein inhibitors pertussis toxin (PTX) and cholera toxin (CTX) also prevented the ET-1 response; however, strong membrane depolarization with KCl (30 mmol/L) subsequently induced sustained increase of [Ca]cand [Ca]n. Pretreatment of hVSMCs with either the PKC activator phorbol-12,13-dibutyrate or the PKC inhibitor bisindolylmaleimide did not affect ET-1-induced sustained increase of intracellular Ca2+. These results suggest that both ETA- and ETB-receptor activation contribute to ET-1-induced sustained increase of [Ca]cand [Ca]nin hVSMCs. Moreover, in contrast to the peptidic antagonists of ET-1 receptors, the nonpeptidic ETA-receptor antagonist BMS-182874 and the nonpeptidic ETB-receptor antagonist A-192621 were able to reverse the effect of ET-1. Nonpeptidic ETA- and ETB-receptor antagonists may therefore be better pharmacological tools for blocking ET-1-induced sustained increase of intracellular Ca2+in hVSMCs. Our results also suggest that the ET-1-induced sustained increase of [Ca]cand [Ca]nis not mediated via activation of PKC, but via a PTX- and CTX-sensitive G protein calcium influx through the R-type Ca2+channel.
Urinary protein profiling with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry in ETBreceptor-deficient ratsThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Raila Jens , Kalk Philipp , Pfab Thiemo , Thöne-Reineke Christa , Godes Michael , Yanagisawa Masashi , Schweigert Florian J. , Hocher Berthold 
Published: August 2008

The pathways leading to salt-sensitive hypertension and renal damage in rescued ETBreceptor-deficient (ETBRd) rats are still unknown. The objective of the study was therefore to identify modifications of urinary peptide and protein expression in ETBRd rats (n = 9) and wild-type controls (n = 6) using SDS – polyacrylamide gel electrophoresis (SDS-PAGE) and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology. Glomerular filtration rate, glomerulosclerosis, and tubulointerstitial fibrosis did not differ between the groups. ETBRd rats showed slightly higher blood pressure (p < 0.001), media/lumen ratio of intrarenal arteries (p < 0.01), and albuminuria (p < 0.01). SDS-PAGE confirmed albuminuria, but showed no differences in the urinary excretion of low molecular weight proteins (<60 kDa). SELDI-TOF-MS profiling revealed 9 proteomic features at molecular masses (Da) of 2720, 2980, 3130, 3345, 6466, 6682, 8550, 18 729, and 37 492, which were significantly elevated (p < 0.02) in urine of ETBRd rats. The results demonstrate that, independent of structural changes in the kidneys, ETB-receptor deficiency causes specific differences in urinary peptide and protein excretion. SELDI-TOF-MS may be a valuable tool for the characterization of urinary biomarkers helping to uncover the mechanism of ETBR action in the kidney.
Effect of the putative novel selective ETA-receptor antagonist HJP272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one, on infection-mediated premature deliveryThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Olgun Nicole , Patel Hardik J. , Stephani Ralph , Wang Wei , Yen Haoting , Reznik Sandra E. 
Published: August 2008

Preterm birth (PTB), defined as any birth occurring before 37 weeks of gestation, occurs in only 12% of all births, yet accounts for nearly half of long-term neurological morbidity, and 60%–80% of perinatal mortality. The single most common cause of PTB is intrauterine infection. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is both upregulated by inflammatory cytokines and capable of increasing myometrial smooth muscle tone. We hypothesized, therefore, that ET-1 is a critical component of the parturition cascade in the setting of infection-associated PTB. In our previous work, we have shown that blockade of ET-1 synthesis through the use of the metalloproteinase inhibitor phosphoramidon results in control of preterm labor. In the current work, we showed that blockade of ET-1 action with 5–50 mg/kg i.p. 3-(3-carboxybenzyl)-1-((6-ethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (HJP272), a putative novel selective ETA-receptor antagonist (IC50, 70 nmol/L), prevents PTB induced with up to 50 mg/kg of i.p. lipopolysaccharide in a mouse model. This is the first report, to our knowledge, of control of infection-associated PTB with a specific ETA-receptor antagonist. The identification of a novel effective therapy for PTB could have important clinical implications.
Refractoriness of sural nerve in humans
Authors: Stevens Paige , Bawa Parveen 
Published: August 2008

High-frequency stimulation of peripheral nerve bundles is frequently used in clinical tests and physiologic experiments to study presynaptic and postsynaptic effects. To understand the postsynaptic effects, it is important to ensure that each pulse in the train is equally effective in stimulating the presynaptic nerve bundle; however, the optimal interpulse interval (IPI) and the stimulus intensity at which each pulse is equally effective in stimulating the same number of axons are not known. The magnitude of the compound action potential produced by each pulse in a train was tested on the sural nerve of 4 healthy human subjects. The stimulus train (2–4 pulses) was applied to the sural nerve at the lateral malleolus, and neural responses were recorded from just below the knee. With 2-pulse trains, families of curves between IPIs (1–6 ms) and normalized amplitudes of the second response were plotted for different stimulus intensities. Visual inspection of the data showed that the curves fell into 2 groups: with stimulus intensities <2.5× perception threshold (Th), the test response appeared partially at longer IPIs, whereas with stimulus intensities ≥3× Th, partial recovery of the test response was earlier. The interval for complete recovery was statistically the same for low- and high-intensity stimulation. With more than 2 pulses in a stimulus train (IPI = 5 ms), the amplitude of the compound action potential (CAP) was not affected significantly. These results are important in understanding both the presynaptic and postsynaptic responses when presynaptic axon bundles are stimulated at high frequencies.
Changes of action potential and L-type calcium channel current of Sprague–Dawley rat ventricular myocytes by different amlodipine isomers
Authors: Wang Ru-xing , Jiang Wen-ping 
Published: August 2008

To investigate the effects of S- and R-amlodipine (Aml) on action potential (AP) and L-type calcium channel current (ICa-L), the whole-cell patch-clamp technique was used on rat ventricular myocytes to record AP, ICa-L, peak currents, steady-state activation currents, steady-state inactivation currents, and recovery currents from inactivation with S-Aml and R-Aml at various concentrations. Increasing concentrations of S-Aml gradually shortened AP durations (APDs). At concentrations of 0.1, 0.5, 1, 5, and 10 μmol/L, S-Aml blocked 1.5% ± 0.2%, 25.4% ± 5.3%, 65.2% ± 7.3%, 78.4% ± 8.1%, and 94.2% ± 5.0% of ICa-L, respectively (p < 0.05), and the half-inhibited concentration was 0.62 ± 0.12 µmol/L. Current–voltage curves were shifted upward; steady-state activation and inactivation curves were shifted to the left. At these concentrations of S-Aml, the half-activation voltages were –16.01 ± 1.65, –17.61 ± 1.60, –20.17 ± 1.46, –21.87 ± 1.69, and –24.09 ± 1.87 mV, respectively, and the slope factors were increased (p < 0.05). The half-inactivation voltages were –27.16 ± 4.48, –28.69 ± 4.52, –31.19 ± 4.17, –32.63 ± 4.34, and –35.16 ± 4.46 mV, respectively, and the slope factors were increased (p < 0.05). The recovery times from inactivation of S-Aml were prolonged (p < 0.05). In contrast, R-Aml had no effect on AP and ICa-L (p > 0.05) at the concentrations tested. Thus, only S-Aml has calcium channel blockade activity, whereas R-Aml has none of the pharmacologic actions associated with calcium channel blockers.
Simvastatin reverses cardiac hypertrophy caused by disruption of the bradykinin 2 receptorPresented in part at the American College of Cardiology meeting March 2003 in Orlando, USA, and the Society for Pediatric Research meeting May 2007 in Toronto, Canada.
Authors: Osorio Juan C. , Cheema Faisal H. , Martens Timothy P. , Mahmut Naila , Kinnear Caroline , Gonzalez Ana M.D. , Bonney William , Homma Shunichi , Liao James K. , Mital Seema 
Published: August 2008

Bradykinin 2 receptor (B2R) deficiency predisposes to cardiac hypertrophy and hypertension. The pathways mediating these effects are not known. Two-month-old B2R knockout (KO) and wild-type (WT) mice were assigned to 4 treatment groups (n = 12–14/group): control (vehicle); nitro-l-arginine methyl ester (l-NAME) an NO synthase inhibitor; simvastatin (SIM), an NO synthase activator; and SIM+l-NAME. Serial echocardiography was performed and blood pressure (BP) at 6 weeks was recorded using a micromanometer. Myocardial eNOS and mitogen-activated protein kinase (MAPK, including ERK, p38, and JNK) protein expression were measured. Results showed that (i) B2RKO mice had significantly lower ejection fraction than did WT mice (61% ± 1% vs. 73% ± 1%), lower myocardial eNOS and phospho-eNOS, normal systolic BP, and higher LV mass, phospho-p38, and JNK; (ii) l-NAME increased systolic BP in KO mice (117 ± 19 mm Hg) but not in WT mice and exacerbated LV hypertrophy and dysfunction; and (iii) in KO mice, SIM decreased hypertrophy, p38, and JNK, improved function, increased capillary eNOS and phospho-eNOS, and prevented l-NAME-induced LV hypertrophy without lowering BP. We conclude that disruption of the B2R causes maladaptive cardiac hypertrophy with myocardial eNOS downregulation and MAPK upregulation. SIM reverses these abnormalities and prevents the development of primary cardiac hypertrophy as well as hypertrophy secondary to l-NAME-induced hypertension.
Circulating free fatty acids are increased independently of PPARγ activity after administration of poloxamer 407 to mice
Authors: Johnston Thomas P. , Waxman David J. 
Published: August 2008

Poloxamer 407 (P-407) is a copolymer surfactant that induces a dose-controlled dyslipidemia in both mice and rats. Human macrophages cultured with P-407 exhibit a concentration-dependent reduction in cholesterol efflux to apolipoprotein A1 (apoA1) linked to downregulation of the ATP-binding cassette transporter A1 (ABCA1). Activators of peroxisome proliferator-activated receptor gamma (PPARγ), as well as PPARα, increase expression of liver X receptor alpha (LXRα) in macrophages and promote the expression of ABCA1, which, in turn, mediates cholesterol efflux to apoA1. The present study investigated whether P-407 interferes with this signaling pathway. A transactivation assay was used to evaluate whether P-407 can either activate or inhibit the transcriptional activity of PPARγ. Because thiazolidinedione drugs (PPARγ agonists) improve glycemic control in type 2 diabetes by reducing blood glucose concentrations, P-407 was also evaluated for its potential to alter plasma insulin and blood glucose concentrations in wild-type (C57BL/6) and PPARγ-deficient mice. Additionally, because thiazolidinediones attenuate release of free fatty acids (FFAs) from adipocytes and, consequently, decrease circulating plasma levels of FFAs, plasma concentrations of circulating FFAs were also determined in P-407-treated mice. P-407 was unable to modulate PPARγ activity in cell-based transactivation assays. Furthermore, P-407 did not perturb plasma insulin and blood glucose concentrations after administration to mice. However, by an as yet unidentified mechanism, P-407 caused a significant increase in the serum concentration of FFAs in mice beginning 3 h after administration and lasting more than 24 h postdosing. It is concluded that P-407 does not interfere with the functional activity of PPARγ after administration to mice.
Semaphorin-3B Is an Angiogenesis Inhibitor That Is Inactivated by Furin-Like Pro-Protein Convertases
Authors: Varshavsky Asya , Kessler Ofra , Abramovitch Sivan , Kigel Boaz , Zaffryar Shelly , Akiri Gal , Neufeld Gera 
Published: August 2008

Abstract
Semaphorin-3B (sema3B) and semaphorin-3F (sema3F) are secreted tumor suppressors of lung cancer. Sema3F functions as an antiangiogenic factor that repels endothelial cells and compromises their proliferation/survival. However, tumor cells expressing either endogenous or recombinant sema3B fail to repel endothelial cells efficiently. Sema3B found in the conditioned medium of such cells is almost completely cleaved by furin-like pro-protein convertases, generating inactive 61- and 22-kDa fragments. We have generated a sema3B variant that was point mutated at the cleavage site (sema3B-m), thereby conferring partial resistance to cleavage. Conditioned medium from HEK293 cells expressing sema3b-m and conditioned medium of HEK293 cells expressing sema3B contained similar concentrations of semaphorin but sema3B-m was cleaved much less than sema3B. In contrast to HEK293 cells expressing native sema3B, cells expressing sema3b-m strongly repel endothelial cells. Conditioned medium from sema3B-m–expressing cells rapidly caused disassembly of focal adhesions and a collapse of the actin cytoskeleton of endothelial cells, inhibited vascular endothelial growth factor–induced phosphorylation of extracellular signal-regulated kinase 1/2, induced apoptosis of endothelial cells, and inhibited the formation of tubes from endothelial cells in an in vitro angiogenesis assay more potently than conditioned medium from cells expressing sema3B. Furthermore, HEK293 cells expressing sema3B-m inhibited basic fibroblast growth factor–induced angiogenesis in vivo much more potently than cells expressing sema3B. Repulsion of human umbilical vascular endothelial cells by sema3B-m was mediated primarily by the neuropilin-1 (np1) receptor but sema3B-m was also able to transduce signals via neuropilin-2 (np2). These results suggest that up-regulation of furin-like pro-protein convertases in malignant cells may enable tumors to evade the antiangiogenic effects of sema3B. [Cancer Res 2008;68(17):6922–31]
A Stochastic Model for Cancer Stem Cell Origin in Metastatic Colon Cancer
Authors: Odoux Christine , Fohrer Helene , Hoppo Toshitaka , Guzik Lynda , Stolz Donna Beer , Lewis Dale W. , Gollin Susanne M. , Gamblin T. Clark , Geller David A. , Lagasse Eric 
Published: August 2008

Abstract
Human cancers have been found to include transformed stem cells that may drive cancer progression to metastasis. Here, we report that metastatic colon cancer contains clonally derived tumor cells with all of the critical properties expected of stem cells, including self-renewal and the ability to differentiate into mature colon cells. Additionally, when injected into mice, these cells initiated tumors that closely resemble human cancer. Karyotype analyses of parental and clonally derived tumor cells expressed many consistent (clonal) along with unique chromosomal aberrations, suggesting the presence of chromosomal instability in the cancer stem cells. Thus, this new model for cancer origin and metastatic progression includes features of both the hierarchical model for cancerous stem cells and the stochastic model, driven by the observation of chromosomal instability. [Cancer Res 2008;68(17):6932–41]
Glycogen Synthase Kinase 3β Regulates Cell Death Induced by Synthetic Triterpenoids
Authors: Venè Roberta , Larghero Patrizia , Arena Giuseppe , Sporn Michael B. , Albini Adriana , Tosetti Francesca 
Published: August 2008

Abstract
The induction of programmed cell death in premalignant or malignant cancer cells by chemopreventive agents could be a valuable tool to control prostate cancer initiation and progression. In this work, we present evidence that the C-28 methyl ester of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me) induces cell death in androgen-responsive and unresponsive human prostate cancer cell lines at nanomolar and low micromolar concentrations. CDDO-Me induced caspase-3, caspase-8, and caspase-9 activation; poly(ADP-ribose) polymerase cleavage; internucleosomal DNA fragmentation; and loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction in PC3 and DU145 cells. However, caspase-3 and caspase-8 inhibition by Z-DEVD-fmk and Z-IETD-fmk, respectively, or general caspase inhibition by BOC-D-fmk or Z-VAD-fmk did not rescue loss of cell viability induced by CDDO-Me, suggesting the activation of additional caspase-independent mechanisms. Interestingly, CDDO-Me induced inactivating phosphorylation at Ser9 of glycogen synthase kinase 3β (GSK3β), a multifunctional kinase that mediates essential events promoting prostate cancer development and acquisition of androgen independence. The GSK3 inhibitor lithium chloride and, more effectively, GSK3 gene silencing sensitized PC3 and DU145 prostate cancer cells to CDDO-Me cytotoxicity. These data suggest that modulation of GSK3β activation is involved in the cell death pathway engaged by CDDO-Me in prostate cancer cells. [Cancer Res 2008;68(17):6987–96]
Mitochondrial/Cell-Surface Protein p32/gC1qR as a Molecular Target in Tumor Cells and Tumor Stroma
Authors: Fogal Valentina , Zhang Lianglin , Krajewski Stan , Ruoslahti Erkki 
Published: August 2008

AbstractA tumor homing peptide, LyP-1, selectively binds to tumor-associated lymphatic vessels and tumor cells in certain tumors and exhibits an antitumor effect. Here, we show that the protein known as p32 or gC1q receptor is the receptor for LyP-1. Various human tumor cell lines were positive for p32 expression in culture, and the expression was increased in xenograft tumors grown from the positive cell lines. Fluorescence-activated cell sorting analyses with anti-p32 antibodies showed that p32-positive cell lines expressed p32 at the cell surface. These cells bound and internalized LyP-1 peptide in proportion to the cell-surface expression level, which correlated with malignancy rather than total p32 expression in the cells. Like the LyP-1 peptide, p32 antibodies highlighted hypoxic areas in tumors, where they bound to both tumor cells and cells that expressed macrophage/myeloid cell markers and often seemed to be incorporated into the walls of tumor lymphatics. Significant p32 expression was common in human cancers and the p32 levels were often greatly elevated compared with the corresponding normal tissue. These results establish p32, particularly its cell-surface–expressed form, as a new marker of tumor cells and tumor-associated macrophages/myeloid cells in hypoxic/metabolically deprived areas of tumors. Its unique localization in tumors and its relative tumor specificity may make p32 a useful target in tumor diagnosis and therapy. [Cancer Res 2008;68(17):7210–8]