tbuckley/cabot-search huggingface dataset:
Reactive oxygen species and tendinopathy: do they matter?
Authors: C S Bestwick, N Maffulli
Journal: British Journal of Sports Medicine (2004)

Reactive oxygen species are probably involved in tendinopathy

We propose that a molecular link between the exaggerated dysfunctional repair response in overuse tendinopathies and the subsequent orchestration of effective tendon healing is the control of the production and persistence of reactive oxygen species within the intracellular and extracellular milieu of the tendon tissue. Reactive oxygen production and the ensuing cellular response can be strongly influenced by lifestyle factors such as the intensity and frequency of exercise.

“Reactive oxygen species” (ROS; also referred to as active oxygen species, AOS; reactive oxygen intermediates, ROI) is a collective term for both radical and non-radical but reactive species derived from oxygen. A free radical, is “any species capable of independent existence that contains one or more unpaired electrons”.1 The presence of such unpaired electron(s) often imparts considerable reactivity. Commonly detected and potentially physiologically relevant ROS include the superoxide anion, hydrogen peroxide (H2O2), the hydroxyl radical, singlet oxygen, and peroxyl radicals. A further and inter-related group are the reactive nitrogen species (RNS)—for example, peroxynitrite.1

ROS are continually produced during normal cell metabolism. The mitochondrial respiratory chain, NADPH-cytochrome P450 enzymes in the endoplasmic reticulum, phagocytic cells, lipoxygenase, and cyclo-oxygenase are also sources of basal ROS production.1 Trauma and environmental and physiological stimuli may enhance ROS production.1

Traditionally, ROS are viewed as imposing cellular/tissue damage through lipid peroxidation, protein modification, DNA strand cleavage, and oxidative base modification, although the relative reactivity and susceptibility of the molecular targets vary. Thus, ROS production is implicated in numerous aspects of pathophysiology including tumorigenesis, coronary heart disease, autoimmune disease, overuse exercise related damage to muscle, and impairment of fracture healing.1,2

This association with cellular damage and pathology has predisposed much of the literature to consider decreased …
Impact of Repeated Dietary Counseling Between Infancy and 14 Years of Age on Dietary Intakes and Serum Lipids and Lipoproteins
Authors: Harri Niinikoski, Hanna Lagström, Eero Jokinen, Marja Siltala, Tapani Rönnemaa, Jorma Viikari, Olli T. Raitakari, Antti Jula, Jukka Marniemi, Kirsti Näntö-Salonen, Olli Simell
Journal: Circulation (2007)

Background— Atherosclerosis development might be delayed or prevented by dietary measures. The aims of the present study were to evaluate the effect of low-saturated-fat, low-cholesterol dietary counseling on fat intakes, growth, serum cholesterol values, and pubertal development in children and adolescents. Methods and Results— In the randomized prospective Special Turku Coronary Risk Factor Intervention Project (STRIP), a low-saturated-fat, low-cholesterol diet was introduced to intervention infants (n=540) at 7 months of age, and control children (n=522) received an unrestricted diet. Dietary intakes, serum cholesterol values, somatic growth, and development were followed up throughout childhood and adolescence. Saturated fat intakes, serum total cholesterol, and low-density lipoprotein cholesterol values were lower ( P &lt;0.001) in the intervention than in control children during the 14 years, whereas high-density lipoprotein cholesterol values in the 2 study groups showed no difference. Boys had lower total and low-density lipoprotein cholesterol concentrations than girls throughout childhood ( P &lt;0.001), and the intervention effect on serum cholesterol concentration was larger in boys than girls. The 2 study groups showed no difference in growth, body mass index, pubertal development, or age at menarche (median, 13.0 and 12.8 years in the intervention and control girls, respectively; P =0.52). The cholesterol values decreased as puberty progressed. Mean concentrations of total and high-density lipoprotein cholesterol decreased from ≈4.5 and ≈1.4 mmol/L, respectively, in Tanner stage 1 (prepubertal) boys to ≈3.9 and ≈1.1 mmol/L in Tanner stage 4 (late pubertal) boys. Conclusions— Repeated dietary counseling remains effective in decreasing saturated fat and cholesterol intake and serum cholesterol values at least until 14 years of age. Puberty markedly influences serum cholesterol concentrations.
B CELL ACTIVATION IN VIVO BY NONANTIGEN-SPECIFIC INTERACTION WITH T CELLS
Authors: T. Tito, G. M. Shearer, D. Trizio, G. Cudkowicz
Journal: The Journal of Experimental Medicine (1972)

The number of direct (gammaM) hemolytic plaque responses of irradiated mice, repopulated with relatively small and limiting numbers of bone marrow and thymus cells, was increased by the simultaneous immunization with two antigen complexes instead of one. Anti-sheep responses were augmented by the following antigen combinations: SRBC + HRBC, SRBC + BRBC, and SRBC + CRBC. Limiting either thymocytes or bone marrow cells indicated that the antigen mixtures acted at the level of T cells increasing severalfold the number of triggered antigen-reactive cells. It was concluded that one of the antigens could have influenced the triggering of antigen-reactive cells specific for the other by promoting synergistic or derepressive T-T cell interactions. Moreover, bone marrow precursor cells could have been activated by the thymic inducers specific for the test antigens as well as by those specific for the second of the priming antigens.
Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance
Authors: Ron C.J. Schackmann, Miranda van Amersfoort, Judith H.I. Haarhuis, Eva J. Vlug, Vincentius A. Halim, Jeanine M.L. Roodhart, Joost S. Vermaat, Emile E. Voest, Petra van der Groep, Paul J. van Diest, Jos Jonkers, Patrick W.B. Derksen
Journal: Journal of Clinical Investigation (2011)

Metastatic breast cancer is the major cause of cancer-related death among women in the Western world. Invasive carcinoma cells are able to counteract apoptotic signals in the absence of anchorage, enabling cell survival during invasion and dissemination. Although loss of E-cadherin is a cardinal event in the development and progression of invasive lobular carcinoma (ILC), little is known about the underlying mechanisms that govern these processes. Using a mouse model of human ILC, we show here that cytosolic p120-catenin (p120) regulates tumor growth upon loss of E-cadherin through the induction of anoikis resistance. p120 conferred anchorage independence by indirect activation of Rho/Rock signaling through interaction and inhibition of myosin phosphatase Rho–interacting protein (Mrip), an antagonist of Rho/Rock function. Consistent with these data, primary human ILC samples expressed hallmarks of active Rock signaling, and Rock controlled the anoikis resistance of human ILC cells. Thus, we have linked loss of E-cadherin — an initiating event in ILC development — to Rho/Rock-mediated control of anchorage-independent survival. Because activation of Rho and Rock are strongly linked to cancer progression and are susceptible to pharmacological inhibition, these insights may have clinical implications for the development of tailor-made intervention strategies to better treat invasive and metastatic lobular breast cancer.
Comparative study of pituitary-thyroid hormone economy in fasting and hypothyroid rats.
Authors: D L St Germain, V A Galton
Journal: Journal of Clinical Investigation (1985)

Starvation in laboratory rodents results in significant alterations in thyroid hormone economy characterized by decreased circulating levels of thyroxine (T4) and 3,5,3'-triiodothyronine (T3) and a decline in serum thyrotropin (TSH) concentration. To investigate this apparent paradox, we have compared in fasted and hypothyroid animals the intracellular parameters mediating thyroid hormone action in the anterior pituitary gland. In vitro saturation analysis combined with quantitation of nuclear T3 content by radioimmunoassay allowed for characterization of pituitary nuclear T3 receptors and estimation of the endogenous fractional receptor occupancy. In rats, thyroidectomized 4 wk earlier, the 10-fold increase in serum TSH levels and decline in peripheral thyroid hormone concentrations were accompanied by a 61% decrease in pituitary nuclear T3 content and a marked decline in fractional T3 receptor occupancy as compared with control animals. In euthyroid animals subjected to short-term starvation (72 h), serum T3, T4, and TSH levels declined by 52, 43, and 48%, respectively. Despite these marked decreases in circulating thyroid hormone levels, pituitary nuclear T3 content in fasted rats declined by only 15% (P less than 0.05) relative to control levels. This modest decline in nuclear T3 content, combined with a 23% decrease in total T3 receptor number, resulted in an estimated fractional receptor occupancy in fasted animals which was equal to or greater than that noted in controls. The effects of fasting and hypothyroidism on the pituitary were further investigated by quantifying low Michaelis constant (Km) T4 5'-deiodinase activity in the crude cytosol fraction of pituitary homogenates. In thyroidectomized animals, maximum velocity was increased ninefold, whereas fasting resulted in a 37% decrease (P less than 0.025) in this parameter compared with controls. Km values were similar in all experimental groups (4.7 +/- 0.6 nM). These results demonstrate that, despite significant reductions in circulating thyroid hormone concentrations and pituitary T4 5'-deiodinase activity, nuclear T3 levels are maintained at relatively normal levels in the pituitary of the fasted animal and fractional T3 receptor occupancy may actually increase. These findings are in marked contrast to those noted in thyroidectomized animals and suggest that the suppression of TSH secretion accompanying starvation in the rat is mediated, at least in part, by local pituitary mechanisms that serve to maintain and possibly enhance nuclear T3 receptor occupancy.
Integrating computationally assembled mouse transcript sequences with the Mouse Genome Informatics (MGI) database
Authors: Yunxia Zhu, Benjamin L King, Babak Parvizi, Brian P Brunk, Christian J Stoeckert, John Quackenbush, Joel Richardson, Carol J Bult
Journal: Genome biology (2003)

Databases of experimentally generated and computationally derived transcript sequences are valuable resources for genome analysis and annotation. The utility of such databases is enhanced when the sequences they contain are integrated with such biological information as genomic location, gene function, gene expression and phenotypic variation. We present the analysis and results of a semi-automated process of connecting transcript assemblies with highly curated biological information for mouse genes that is available through the Mouse Genome Informatics (MGI) database.
Calibration of Avian Molecular Clocks
Authors: Marcel van Tuinen, S. Blair Hedges
Journal: Molecular Biology and Evolution (2001)

Molecular clocks can be calibrated using fossils within the group under study (internal calibration) or outside of the group (external calibration). Both types of calibration have their advantages and disadvantages. An internal calibration may reduce extrapolation error but may not be from the best fossil record, raising the issue of nonindependence. An external calibration may be more independent but also may have a greater extrapolation error. Here, we used the advantages of both methods by applying a sequential calibration to avian molecular clocks. We estimated a basal divergence within birds, the split between fowl (Galliformes) and ducks (Anseriformes), to be 89.8 +/- 6.97 MYA using an external calibration and 12 rate-constant nuclear genes. In turn, this time estimate was used as an internal calibration for three species-rich avian molecular data sets: mtDNA, DNA-DNA hybridization, and transferrin immunological distances. The resulting time estimates indicate that many major clades of modern birds had their origins within the Cretaceous. This supports earlier studies that identified large gaps in the avian fossil record and suggests that modern birds may have coexisted with other avian lineages for an extended period during the Cretaceous. The new time estimates are concordant with a continental breakup model for the origin of ratites.
Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease. Comparative effects of ACE inhibition and calcium channel blockade.
Authors: G M London, B Pannier, A P Guerin, S J Marchais, M E Safar, J L Cuche
Journal: Circulation (1994)

BACKGROUND We wished to assess the respective roles of the antihypertensive and blood pressure (BP)-independent effects of antihypertensive drugs on arterial hemodynamics and left ventricular hypertrophy (LVH) in end-stage renal disease (ESRD) patients. METHODS AND RESULTS In a double-blind study, 24 ESRD patients with LVH were randomized to 12 months' administration of either the angiotensin-converting enzyme (ACE) inhibitor perindopril (n = 14) or the calcium channel blocker nitrendipine (n = 10). Repeated measurements of the following parameters were performed: BP (mercury sphygmomanometry), left ventricular mass (LVM, echocardiography), cardiac output (aortic cross-section and velocity integral), total peripheral resistance (cardiac output and mean BP), aortic and large-artery compliance (pulse wave velocity, Doppler flowmeter), and arterial wave reflections (augmentation index, applanation tonometry). Radioimmunoassay was used to determine plasma renin activity, aldosterone, and plasma catecholamine levels. Two-way (time-treatment) ANOVA for repeated measures was used for statistical analysis. Perindopril and nitrendipine induced significant and similar decreases in BP, total peripheral resistance (P &lt; .001), aortic and arterial pulse wave velocities (P &lt; .001), and arterial wave reflections (P &lt; .01). At baseline, the two groups had LVH mostly due to increased LV end-diastolic diameter (LVEDD) (perindopril, 54.3 +/- 1.4 and nitrendipine, 54.3 +/ 2.4 mm) with near-normal mean LV wall thickness (perindopril, 11.4 +/- 0.3 and nitrendipine, 11.2 +/- 0.4 mm). A decrease in LVM was observed only in patients receiving perindopril (from 317 +/- 18 to 247 +/- 21 g) (time-treatment interaction, P = .036). Nitrendipine had no significant effect on LVM (314 +/- 29 versus 286 +/- 32 g). The decrease in LVM observed with perindopril was associated with a reduction in LVEDD (49.9 +/- 1.6 versus 54.3 +/- 1.4 mm after 12 months) (time-treatment interaction, P = .04), while the mean LV wall thickness was unchanged (11.4 +/- 0.3 versus 10.5 +/- 0.5 mm). Cardiac alterations were not correlated with changes in BP or with alterations in plasma renin activity or aldosterone or catecholamine levels. CONCLUSIONS In ESRD patients with LVH, ACE inhibition decreases LVM independently of its antihypertensive effect and of associated alterations in arterial hemodynamics. The decrease in LVM was due primarily to a decrease in LV volume, which may have resulted in these patients from chronic volume overload.
Endocrinological derangement in COPD
Authors: S. Andreas
Journal: European Respiratory Journal (2010)

To the Editors :

With the greatest interest I have read the comprehensive review “endocrinological derangements” in chronic obstructive pulmonary disease (COPD) by Laghi et al. 1. Arriving at the last page, where the authors discussed the renin–angiotensin–aldosterone system, I have read: “the presence of sympathetic neuropathy…” and “…the possibility that autonomic neuropathy is caused by intraneural hypoxaemia”.

In COPD and other …
Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease
Authors: J Vestbo
Journal: Thorax (2005)

<b>Background:</b> Combined treatment with inhaled corticosteroids and long acting β<sub>2</sub> agonists is approved for the treatment of chronic obstructive pulmonary disease (COPD), but little is known about the onset of effect of the combination. <b>Methods:</b> Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow (PEF) and symptom scores. <b>Results:</b> PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo. In patients treated with fluticasone propionate 500 μg twice daily alone, PEF differed from placebo after 2 days. The differences after 2 weeks compared with placebo were 16 l/min (95% confidence interval (CI) 11 to 21), 11 l/min (95% CI 6 to 16), and 27 l/min (95% CI 22 to 33) for salmeterol, fluticasone propionate, and the salmeterol/fluticasone propionate combination, respectively. For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study. The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second (FEV<sub>1</sub>). Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group. The 2 week change in FEV<sub>1</sub> was only partly indicative of a long term response in individual patients. <b>Conclusions:</b> The effects of salmeterol and fluticasone propionate, alone or in combination, on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks.
A Cyclin D2–Rb Pathway Regulates Cardiac Myocyte Size and RNA Polymerase III After Biomechanical Stress in Adult Myocardium
Authors: Ekaterini Angelis, Alejandro Garcia, Shing S. Chan, Katja Schenke-Layland, Shuxen Ren, Sarah J. Goodfellow, Maria C. Jordan, Kenneth P. Roos, Robert J. White, W. Robb MacLellan
Journal: Circulation Research (2008)

Normally, cell cycle progression is tightly coupled to the accumulation of cell mass; however, the mechanisms whereby proliferation and cell growth are linked are poorly understood. We have identified cyclin (Cyc)D2, a G(1) cyclin implicated in mediating S phase entry, as a potential regulator of hypertrophic growth in adult post mitotic myocardium. To examine the role of CycD2 and its downstream targets, we subjected CycD2-null mice to mechanical stress. Hypertrophic growth in response to transverse aortic constriction was attenuated in CycD2-null compared with wild-type mice. Blocking the increase in CycD2 in response to hypertrophic agonists prevented phosphorylation of CycD2-target Rb (retinoblastoma gene product) in vitro, and mice deficient for Rb had potentiated hypertrophic growth. Hypertrophic growth requires new protein synthesis and transcription of tRNA genes by RNA polymerase (pol) III, which increases with hypertrophic signals. This load-induced increase in RNA pol III activity is augmented in Rb-deficient hearts. Rb binds and represses Brf-1 and TATA box binding protein (TBP), subunits of RNA pol III-specific transcription factor B, in adult myocardium under basal conditions. However, this association is disrupted in response to transverse aortic constriction. RNA pol III activity is unchanged in CycD2(-/-) myocardium after transverse aortic constriction, and there is no dissociation of TBP from Rb. These investigations identify an essential role for the CycD2-Rb pathway as a governor of cardiac myocyte enlargement in response to biomechanical stress and, more fundamentally, as a regulator of the load-induced activation of RNA pol III.
Circumferential stretching of saphenous vein smooth muscle enhances vasoconstrictor responses by Rho kinase-dependent pathways
Authors: E McGregor
Journal: Cardiovascular Research (2002)

Objective: Surgical preparation and/or pulsatile arterial perfusion of saphenous vein increases the sensitivity of vein rings to calcium mobilising agonists such as phenylephrine. We have investigated the mechanism(s) underlying this effect. Methods: We have used an ex vivo flow circuit, with simulated arterial or venous flows (mean pressure 100 and 20 mmHg, respectively), to investigate the sensitivity of human saphenous vein to phenylephrine, 5-hydroxytryptamine (5-HT) and KCl, using organ chamber pharmacology. Results: After 90 min of pulsatile arterial perfusion the mean maximum tension induced by KCl had increased from 4.7 to 11.1 g (n=5), by phenylephrine had increased from 4.4 to 10.2 g (n=8) and by 5-HT had increased from 4.4 to 6.7 g (n=10), all P<0.01. Phenylephrine did not augment the tension in vein rings maximally precontracted with KCl (n=4). The EC50 for KCl was unchanged after pulsatile arterial perfusion (n=5), but for phenylephrine and 5-HT there were significant reductions from 14±5 to 2±1 μM (n=8) and from 1.0±0.4 to 0.20±0.06 μM (n=10), respectively. The rate of contraction (in response to 3 μM phenylephrine) increased from 0.11 g/min to 0.37 g/min, P<0.02, after arterial perfusion (n=4). These changes in contractile properties (to phenylephrine) were endothelium-independent, evident within 5 min of simulated arterial perfusion. The changes in contractile properties could be abrogated by external stenting of the vein (to attenuate circumferential deformation) or inclusion in the perfusate of a vasodilator, e.g., cromakalim (5 μM) or the selective Rho kinase inhibitor Y-27632 (20 μM). The heightened sensitivity and contractility to phenylephrine was maintained after inclusion of adenosine (100 μM), gadolinium (10 μM) or cycloheximide (10 μM) in the vein perfusate. Conclusions: The circumferential deformations imposed by simulated arterial perfusion alter the vasomotor responses of saphenous vein smooth muscle. These effects are independent of new protein synthesis or the activation of stretch activated cation channels. The Rho kinase pathway appears to mediate the signalling mechanisms leading to increased agonist-induced tension and the increased sensitivity to vasoconstrictors.
A Rare Polymorphic Variant of <i>NBS1</i> Reduces DNA Repair Activity and Elevates Chromosomal Instability
Authors: Yuki Yamamoto, Mamiko Miyamoto, Daisuke Tatsuda, Michiaki Kubo, Hitoshi Nakagama, Yusuke Nakamura, Hitoshi Satoh, Koichi Matsuda, Toshiki Watanabe, Tsutomu Ohta
Journal: Cancer Research (2014)

Failure to expeditiously repair DNA at sites of double-strand breaks (DSB) ultimately is an important etiologic factor in cancer development. NBS1 plays an important role in the cellular response to DSB damage. A rare polymorphic variant of NBS1 that resulted in an isoleucine to valine substitution at amino acid position 171 (I171V) was first identified in childhood acute lymphoblastic leukemia. This polymorphic variant is located in the N-terminal region that interacts with other DNA repair factors. In earlier work, we had identified a remarkable number of structural chromosomal aberrations in a patient with pediatric aplastic anemia with a homozygous polymorphic variant of NBS1-I171V; however, it was unclear whether this variant affected DSB repair activity or chromosomal instability. In this report, we demonstrate that NBS1-I171V reduces DSB repair activity through a loss of association with the DNA repair factor MDC1. Furthermore, we found that heterozygosity in this polymorphic variant was associated with breast cancer risk. Finally, we showed that this variant exerted a dominant-negative effect on wild-type NBS1, attenuating DSB repair efficiency and elevating chromosomal instability. Our findings offer evidence that the failure of DNA repair leading to chromosomal instability has a causal impact on the risk of breast cancer development.