tbuckley/cabot-search huggingface dataset:
Identification of the thromboxane A2 receptor in hepatic sinusoidal endothelial cells and its role in Endotoxin-induced liver injury in rats
Authors: Satoshi Ishiguro, Shigeki Arii, Kazunobu Monden, Yukito Adachi, Naomi Funaki, Hiroaki Higashitsuji, Shin-Ichi Fujita, Masaharu Furutani, Masahiro Mise, Tadahiro Kitao, Toshio Nakamura, Fumitaka Ushikubi, Ken-Ichi Nakamura, Shuh Narumiya, Katsuhiko Enomoto, Tousei Ohmura, Michio Mori, Masayuki Imamura
Journal: Hepatology (1994)

The presence of the thromboxane A2 receptor in sinusoidal endothelial cells was investigated and its pathogenic role in endotoxin-induced liver injury examined. The receptor was measured with a binding assay using a specific thromboxane A2 receptor antagonist, [3H]S-145. Scatchard analysis of the binding indicated the presence of a single class of high-affinity binding sites with a dissociation constant of 5.00 +/- 0.96 nmol/L, a maximal binding of 22.85 +/- 2.71 fmol/10(6) cells and 13.80 +/- 1.60 x 10(3) binding sites per cell. The addition of a cyclooxygenase inhibitor, indomethacin, during the cell preparation increased the maximal binding value and the number of binding sites of 37.34 +/- 3.01 and 22.50 +/- 1.80 x 10(3) sites/cell, respectively. The binding was displaced by various thromboxane A2 analogs such as ONO-3708 and STA2 but was not effectively competed for by other prostaglandins. Endotoxin injection reduced dissociation constant, maximal binding and the number of binding sites in sinusoidal endothelial cells to 3.49 +/- 0.87 nmol/L, 6.03 +/- 0.64 fmol/10(6) cells and 3.65 +/- 0.39 x 10(3) sites/cell, respectively. A cyclooxygenase inhibitor and a Kupffer cell inhibitor added before endotoxin treatment significantly prevented the reduction in the number of thromboxane A2 receptors. It is possible that these effects were due to a reduction in the agonist-induced internalization of the thromboxane A2 receptor brought about by the prevention of thromboxane A2 production. Preadministration of both a cyclooxygenase inhibitor and a thromboxane A2 receptor antagonist attenuated the degree of endotoxin-induced liver injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II Induces Premature Senescence of Vascular Smooth Muscle Cells and Accelerates the Development of Atherosclerosis via a p21-Dependent Pathway
Authors: Takeshige Kunieda, Tohru Minamino, Jun-ichiro Nishi, Kaoru Tateno, Tomomi Oyama, Taro Katsuno, Hideyuki Miyauchi, Masayuki Orimo, Sho Okada, Masayuki Takamura, Toshio Nagai, Shuichi Kaneko, Issei Komuro
Journal: Circulation (2006)

Background— Angiotensin II (Ang II) has been reported to contribute to the pathogenesis of various human diseases including atherosclerosis, and inhibition of Ang II activity has been shown to reduce the morbidity and mortality of cardiovascular diseases. We have previously demonstrated that vascular cell senescence contributes to the pathogenesis of atherosclerosis; however, the effects of Ang II on vascular cell senescence have not been examined. Methods and Results— Ang II significantly induced premature senescence of human vascular smooth muscle cells (VSMCs) via the p53/p21-dependent pathway in vitro. Inhibition of this pathway effectively suppressed induction of proinflammatory cytokines and premature senescence of VSMCs by Ang II. Ang II also significantly increased the number of senescent VSMCs and induced the expression of proinflammatory molecules and of p21 in a mouse model of atherosclerosis. Loss of p21 markedly ameliorated the induction of proinflammatory molecules by Ang II, thereby preventing the development of atherosclerosis. Replacement of p21 -deficient bone marrow cells with wild-type cells had little influence on the protective effect of p21 deficiency against the progression of atherogenesis induced by Ang II. Conclusions— We demonstrated that Ang II promotes vascular inflammation by inducing premature senescence of VSMCs both in vitro and in vivo. Our results suggest a critical role of p21-dependent premature senescence of VSMCs in the pathogenesis of atherosclerosis.
Asymmetric dimethylarginine and asthma
Authors: Jeremy A. Scott, Gail M. Gauvreau, Hartmut Grasemann
Journal: European Respiratory Journal (2014)

To the Editor: 

With interest we have read the letter by Lau et al. [1] regarding circulating asymmetric dimethylarginine (ADMA) in a cohort of children with asthma from the Australian Childhood Asthma Prevention Study.

ADMA, a product of protein degradation, is an endogenous nitric oxide synthase inhibitor that has been shown to be increased in mouse models of allergic airway inflammation and to be associated with airways hyperresponsiveness in these animals [2]. ADMA has also been reported to be increased in sputum samples [2] and exhaled breath condensates [3] from paediatric patients with asthma. Increased ADMA in serum has recently been found to be associated with the severity of symptoms in late-onset asthma and obesity [4].

Lau et al. [1] found no difference in …
Relaxation properties of mammalian atrial muscle.
Authors: M M Couttenye, N M De Clerck, M A Goethals, D L Brutsaert
Journal: Circulation Research (1981)

The properties of relaxation, particular the sensitivity of relaxation to load, were analyzed in isolated intact atrial muscle and in manually dissected, detergent-treated cellular preparations from cat, dog, and rat atria. Force and length traces under increasing afterloads and following load clamps were obtained using an electromagnetic lever-force transducer system for the intact muscles and a capacitance transducer system for the cellular preparations. In both types of preparations, the time course of relaxation was hardly affected by the load or by alterations in load (load clamps), unlike intact mammalian ventricular muscle. This load independence of relaxation, which was hardly influenced by variations of initial muscle length, resembled relaxation in intact frog ventricular muscle and in detergent-treated mammalian ventricular single cells. As relaxation of these ventricular preparations with poorly developed (frog) or absent (detergent-treated single cells) calcium-sequestering systems was shown to be governed by the dissipation of activation, these results suggest a similar control mechanism for relaxation in mammalian atrial muscle. Furthermore, load independence of relaxation of mammalian atrial muscle in late diastole may promote optimal filling of the ventricle.
Combined therapy for pyoderma gangrenosum
Authors: A P Rozin
Journal: Annals of the Rheumatic Diseases (2004)

We report a case of successful combined therapy for rapidly progressive pyoderma gangrenosum (PG). A 78 year old woman was admitted to the department of rheumatology with large right leg skin ulcers affecting the anterior and mediolateral lower shin region (fig 1A). The lesions had developed from small pustules to a focus of large painful skin damage during the past month. Her past history was free of any skin disease. Arterial hypertension, depression, and osteoporosis were controlled with permanent treatment. Her laboratory findings were unremarkable, including negative hepatitis B surface antigen and hepatitis C virus and normal liver function.



 Figure 1  
 (A) Large ulcers of pyoderma gangrenosum with an irregular, well defined, undermined, partially raised violaceous border on admission. (B) Complete healing of the wound after combined prednisone-cyclosporin A-pulse cyclophosphamide …
Adjuvant Chemotherapy for Stage II Colon Cancer: Less Complicated Than We Thought
Authors: Rachel S. Midgley, David J. Kerr
Journal: Journal of Clinical Oncology (2013)

In his recent editorial, Mayer 1 agreed with the conclusion of Tournigand et al 2 that there is no benefit for the inclusion of oxaliplatin in adjuvant chemotherapy regimens for patients with standard or indeed high-risk stage II colon cancer.Mayer then posed the question as to whether these patients, with a generally favorable prognosis, merit any adjuvant treatment at all.The virtues of prolonged clinical trial follow-up to provide mature survival data were extolled, but it surprised us greatly that no mention was made of Quasar (Quick and Simple and Reliable) 1 (A UKCCR[United Kingdom Coordinating Committee on Cancer Research] Study of Adjuvant Chemotherapy for Colorectal Cancer), the only trial in this field to show a survival benefit for patients with stage II colon cancer.In the Quasar 1 study, 2,291 patients with colon cancer were randomly assigned to receive chemotherapy with fluorouracil and leucovorin or to undergo observation.After a median follow-up of 5.5 years, the trial demonstrated that although the absolute improvements are small, the relative risk of death that was observed translates into a significant absolute improvement in survival of 3.6% (95% CI, 1.0 to 6.0; P ϭ .04).This is by far the largest and therefore the most informative trial of chemotherapy ever undertaken for this disease, and it is the only trial to show a significant survival benefit. 3 The fluorouracil-based chemotherapy was well tolerated, and we believe that these results are sufficient to mandate an informed discussion with all patients with stage II colon cancer so that at least the offer of treatment might be made.Furthermore, we have worked with colleagues from the National Surgical Adjuvant Breast and Bowel Project, the Cleveland Clinic, and Genomic Health to develop a polymerase chain reactionbased prognostic gene signature that has now been validated in more than 5,000 patients.This can be used to define the risk of recurrence with greater precision than conventionally accepted high-risk criteria, and therefore can inform and influence the outcome of the physicianpatient consultation. 4 We believe that there are data and validated tools that support rational and informed decision making on the utility of adjuvant fluorouracil-based therapy for patients with stage II colon cancer, and that matters are not necessarily as nihilistic as Mayer 1 implies.
Potent leukocidal action of Escherichia coli hemolysin mediated by permeabilization of target cell membranes.
Authors: S Bhakdi, S Greulich, M Muhly, B Eberspächer, H Becker, A Thiele, F Hugo
Journal: The Journal of Experimental Medicine (1989)

The contribution of Escherichia coli hemolysin (ECH) to bacterial virulence has been considered mainly in context with its hemolytic properties. We here report that this prevalent bacterial cytolysin is the most potent leukocidin known to date. Very low concentrations (approximately 1 ng/ml) of ECH evoke membrane permeability defects in PMN (2-10 x 10(6) cells/ml) leading to an efflux of cellular ATP and influx of propidium iodide. The attacked cells do not appear to repair the membrane lesions. Human serum albumin, high density and low density lipoprotein, and IgG together protect erythrocytes and platelets against attack by even high doses (5-25 micrograms/ml) of ECH. In contrast, PMN are still permeabilized by ECH at low doses (50-250 ng/ml) in the presence of these plasma inactivators. Thus, PMN become preferred targets for attack by ECH in human blood and protein-rich body fluids. Kinetic studies demonstrate that membrane permeabilization is a rapid process, ATP-release commencing within seconds after application of toxin to leukocytes. It is estimated that membrane permeabilization ensues upon binding of approximately 300 molecules ECH/PMN. This process is paralleled by granule exocytosis, and by loss of phagocytic killing capacity of the cells. The recognition that ECH directly counteracts a major immune defence mechanism of the human organism through its attack on granulocytes under physiological conditions sheds new light on its possible role and potential importance as a virulence factor of E. coli.
Decoy Receptor DcR1 Is Induced in a p50/Bcl3–Dependent Manner and Attenuates the Efficacy of Temozolomide
Authors: Nassir M. Mansour, Giovanna M. Bernal, Longtao Wu, Clayton D. Crawley, Kirk E. Cahill, David J. Voce, Irina V. Balyasnikova, Wei Zhang, Ruben Spretz, Luis Nunez, Gustavo F. Larsen, Ralph R. Weichselbaum, Bakhtiar Yamini
Journal: Cancer Research (2015)

Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53(+/+) glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.
Downregulation of SnoN Expression in Obstructive Nephropathy Is Mediated by an Enhanced Ubiquitin-Dependent Degradation
Authors: Ruoyun Tan, Jinglan Zhang, Xiaoyue Tan, Xianghong Zhang, Junwei Yang, Youhua Liu
Journal: Journal of the American Society of Nephrology (2006)

Smad transcriptional co-repressor SnoN acts as an antagonist that tightly controls the trans-activation of TGF-beta/Smad target genes. SnoN protein is reduced progressively in the fibrotic kidney after obstructive injury, suggesting that the loss of Smad antagonist is a critical event that leads to an uncontrolled fibrogenic signaling. However, the mechanism underlying SnoN downregulation remains unknown. This study investigated the regulation and mechanism of renal SnoN expression in vivo. Whereas SnoN protein was markedly diminished, its mRNA levels remained relatively constant in the obstructed kidney after ureteral ligation. An increased ubiquitination and proteasome-dependent degradation of SnoN was found in obstructed kidney, compared with sham controls. Smad ubiquitination regulatory factor-2, an E3 ubiquitin ligase, was induced and formed a complex with SnoN in vivo. In vitro, TGF-beta1 promoted SnoN protein degradation, which was mediated by ubiquitination and a proteasome-dependent mechanism. SnoN constitutively interacted with another Smad co-repressor, Ski, and they formed ternary complex with Smad2/3 upon TGF-beta1 stimulation. However, ectopic expression of Ski did not alter the degradation rate of SnoN. Blockage of SnoN degradation by proteasome inhibitor abolished TGF-beta1-mediated alpha-smooth muscle actin and fibronectin induction, suggesting that SnoN degradation could be necessary for TGF-beta1 to exert its fibrogenic action. Furthermore, knockdown of Smad ubiquitination regulatory factor-2 expression by small interfering RNA strategy led to an increase in SnoN abundance and inhibited the TGF-beta1-mediated gene transcription. These results indicate that downregulation of SnoN expression in the obstructed kidney is mediated by an enhanced ubiquitin-dependent degradation. Preservation of SnoN by inhibiting its degradation may be a novel strategy for targeting hyperactive Smad signaling in renal fibrotic diseases.
Oral magnesium therapy, exercise heart rate, exercise tolerance, and myocardial function in coronary artery disease patients
Authors: R Pokan, P Hofmann, S P von Duvillard, G Smekal, M Wonisch, K Lettner, P Schmid, M Shechter, B Silver, N Bachl
Journal: British Journal of Sports Medicine (2006)

Previous studies have demonstrated that in patients with coronary artery disease (CAD) upward deflection of the heart rate (HR) performance curve can be observed and that this upward deflection and the degree of the deflection are correlated with a diminished stress dependent left ventricular function. Magnesium supplementation improves endothelial function, exercise tolerance, and exercise induced chest pain in patients with CAD.We studied the effects of oral magnesium therapy on exercise dependent HR as related to exercise tolerance and resting myocardial function in patients with CAD.In a double blind controlled trial, 53 male patients with stable CAD were randomised to either oral magnesium 15 mmol twice daily (n = 28, age 61+/-9 years, height 171+/-7 cm, body weight 79+/-10 kg, previous myocardial infarction, n = 7) or placebo (n = 25, age 58+/-10 years, height 172+/-6 cm, body weight 79+/-10 kg, previous myocardial infarction, n = 6) for 6 months. Maximal oxygen uptake (VO2max), the degree and direction of the deflection of the HR performance curve described as factor k<0 (upward deflection), and the left ventricular ejection fraction (LVEF) were the outcomes measured.Magnesium therapy for 6 months significantly increased intracellular magnesium levels (32.7+/-2.5 v 35.6+/-2.1 mEq/l, p<0.001) compared to placebo (33.1+/-3.1.9 v 33.8+/-2.0 mEq/l, NS), VO2max (28.3+/-6.2 v 30.6+/-7.1 ml/kg/min, p<0.001; 29.3+/-5.4 v 29.6+/-5.2 ml/kg/min, NS), factor k (-0.298+/-0.242 v -0.208+/-0.260, p<0.05; -0.269+/-0.336 v -0.272+/-0.335, NS), and LVEF (58+/-11 v 67+/-10%, p<0.001; 55+/-11 v 54+/-12%, NS).The present study supports the intake of oral magnesium and its favourable effects on exercise tolerance and left ventricular function during rest and exercise in stable CAD patients.
Evolutionary Dynamics of Multiple Group I Introns in Nuclear Ribosomal RNA Genes of Endoparasitic Fungi of the Genus Cordyceps
Authors: Naruo Nikoh, Takema Fukatsu
Journal: Molecular Biology and Evolution (2001)

A large number of group I introns were discovered in coding regions of small and large subunits of nuclear ribosomal RNA genes (SSU rDNA and LSU rDNA) in ascomycetous fungi of the genus Cordyceps. From 28 representatives of the genus, we identified in total 69 group I introns which were inserted at any of four specific sites in SSU rDNA and four specific sites in LSU rDNA. These group I introns reached sizes of up to 510 bp, occurred in up to eight sites in the same organism, and belonged to either subgroup IB3 or subgroup IC1 based on their sequence and structure. Introns inserted at the same site were closely related to each other among Cordyceps fungi, whereas introns inserted at different sites were phylogenetically distinct even in the same species. Mapped on the host phylogeny, the group I introns were generally not restricted to a particular lineage, but, rather, widely and sporadically distributed among distinct lineages. When the phylogenetic relationships of introns inserted at the same site were compared with the phylogeny of their hosts, the topologies were generally significantly congruent to each other. From these results, the evolutionary dynamics of multiple group I introns in Cordyceps fungi was inferred as follows: (1) most of the group I introns were already present at the eight sites in SSU and LSU rDNAs of the ancestor of the genus Cordyceps; (2) the introns have principally been immobile and vertically transmitted throughout speciation and diversification of Cordyceps fungi, which resulted in the phylogenetic congruence between the introns at the same site and their hosts; (3) in the course of vertical transmission, the introns have repeatedly been lost in a number of lineages independently, which has led to the present sporadic phylogenetic distribution of the introns; and (4) a few acquisitions of new introns, presumably through horizontal transmission, were identified in the evolutionary history of the genus Cordyceps, while no transpositions were detected. Losses of group I introns in SSU rDNA have occurred at least 27 times in the evolutionary course of the 28 Cordyceps members.
C-Reactive Protein Levels Following Acute Myocardial Infarction
Authors: Vincent W. Wong, Mark McLean, Steven C. Boyages, N. Wah Cheung
Journal: Diabetes Care (2004)

Acute myocardial infarction (AMI) triggers an inflammatory reaction, which plays an important role in myocardial injury (1). Inflammatory markers such as C-reactive protein (CRP) reflect the extent of myocardial necrosis and correlate with cardiac outcomes following AMI (2–4).

Hyperglycemia has proinflammatory effects, inducing the release of inflammatory cytokines (5) and is associated with increased mortality from AMI (6,7). Conversely, insulin-based therapy in patients following AMI may confer survival benefits, but the mechanism is unclear (8–11). Insulin suppresses the inflammatory response (12), but it is uncertain if the anti-inflammatory effect of insulin therapy depends on glycemic status.

The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI-5) study is a multicentered randomized trial of insulin infusion for hyperglycemic patients with AMI. In this substudy, we examined the relationship between blood glucose levels (BGLs) and the inflammatory response (CRP levels) following AMI and evaluated the effect of insulin-based infusion therapy.

In the HI-5 study, patients presenting with AMI within 24 h who either had known diabetes or admission BGL ≥7.8 mmol/l were recruited. AMI was defined by a plasma troponin T level of 0.1 μg/l. Following written consent, patients were randomized to either intensive or conventional therapy. Intensive therapy consisted of insulin-dextrose infusion for at least 24 h. Patients were given 5% dextrose at 80 ml/h, while …
Metabolic and Hypotensive Effects of Ethacrynic Acid
Authors: R. Patterson Russell
Journal: JAMA (1968)

Twenty-four hypertensive outpatients were randomly allocated and received three successive six-week treatments: placebo, hydrochlorothiazide (200 mg daily), and ethacrynic acid (200 mg daily). Significantly diminished carbohydrate tolerances were observed when tests were conducted after hydrochlorothiazide therapy compared to results of tests conducted after administration of the placebo. Impaired carbohydrate tolerances observed when therapy with ethacrynic acid was compared with the use of placebo were most apparent in subjects with diabetes mellitus. Hydrochlorothiazide and ethacrynic acid effected responses of similar magnitude: pulse rate and serum concentrations of urea nitrogen and uric acid increased; body weight, recumbent and standing blood pressure, and serum concentrations of potassium and chloride decreased.