bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ramipril attenuates lipid peroxidation and cardiac fibrosis in an experimental model of rheumatoid arthritis
Authors: Shi Qin , Abusarah Jamilah , Baroudi Ghayath , Fernandes Julio C , Fahmi Hassan , Benderdour Mohamed 
Published: October 2012

Abstract

Introduction

Recent studies revealed that co-morbidity and mortality due to cardiovascular disease are increased in patients with rheumatoid arthritis (RA) but little is known about factors involved in these manifestations. This study aimed at characterizing the impact of arthritis on oxidative stress status and tissue fibrosis in the heart of rats with adjuvant-induced arthritis (AIA).

Methods

AIA was induced with complete Freund's adjuvant in female Lewis rats. Animals were treated by oral administration of vehicle or angiotensin-converting enzyme inhibitor ramipril (10 mg/kg/day) for 28 days, beginning 1 day after arthritis induction. Isolated adult cardiomyocytes were exposed to 10 μM 4-hydroxynonenal (HNE) for 24 hours in the presence or absence of 10 μM ramipril.

Results

Compared to controls, AIA rats showed significant 55 and 30% increase of 4-HNE/protein adducts in serum and left ventricular (LV) tissues, respectively. Cardiac mitochondrial NADP+-isocitrate dehydrogenase (mNADP-ICDH) activity decreased by 25% in AIA rats without any changes in its protein and mRNA expression. The loss of mNADP-ICDH activity was correlated with enhanced accumulation of HNE/mNADP-ICDH adducts as well as with decrease of glutathione and NADPH. Angiotensin II type 1 receptor (AT1R) expression and tissue fibrosis were induced in LV tissues from AIA rats. In isolated cardiomyocytes, HNE significantly decreased mNADP-ICDH activity and enhanced type I collagen and connective tissue growth factor expression. The oral administration of ramipril significantly reduced HNE and AT1R levels and restored mNADP-ICDH activity and redox status in LV tissues of AIA rats. The protective effects of this drug were also evident from the decrease in arthritis scoring and inflammatory markers.

Conclusion

Collectively, our findings disclosed that AIA induced oxidative stress and fibrosis in the heart. The fact that ramipril attenuates inflammation, oxidative stress and tissue fibrosis may provide a novel strategy to prevent heart diseases in RA.
Prothrombotic effects of tumor necrosis factor alpha in vivo are amplified by the absence of TNF-alpha receptor subtype 1 and require TNF-alpha receptor subtype 2
Authors: Pircher Joachim , Merkle Monika , Wörnle Markus , Ribeiro Andrea , Czermak Thomas , Stampnik Yvonn , Mannell Hanna , Niemeyer Markus , Vielhauer Volker , Krötz Florian 
Published: October 2012

Abstract
Introduction
Elevated serum levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) correlate with an increased risk for atherothrombotic events and TNFα is known to induce prothrombotic molecules in endothelial cells. Based on the preexisting evidence for the impact of TNFα in the pathogenesis of autoimmune disorders and their known association with an acquired hypercoagulability, we investigated the effects of TNFα and the role of the TNF receptor subtypes TNFR1 and TNFR2 for arteriolar thrombosis in vivo.

Methods
Arteriolar thrombosis and platelet-rolling in vivo were investigated in wildtype, TNFR1-/-, TNFR2-/- and TNFR1-/R2-/- C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model. In vitro, expression of prothrombotic molecules was assessed in human endothelial cells by real-time PCR and flow cytometry.

Results
In wildtype mice, stimulation with TNFα significantly accelerated thrombotic vessel occlusion in vivo upon ferric chloride injury. Arteriolar thrombosis was much more pronounced in TNFR1-/- animals, where TNFα additionally led to increased platelet-endothelium-interaction. TNFα dependent prothrombotic effects were not observed in TNFR2-/- and TNFR1-/R2- mice. In vitro, stimulation of human platelet rich plasma with TNFα did not influence aggregation properties. In human endothelial cells, TNFα induced superoxide production, p-selectin, tissue factor and PAI-1, and suppressed thrombomodulin, resulting in an accelerated endothelial dependent blood clotting in vitro. Additionally, TNFα caused the release of soluble mediators by endothelial cells which induced prothrombotic and suppressed anticoagulant genes comparable to direct TNFα effects.

Conclusions
TNFα accelerates thrombus formation in an in vivo model of arteriolar thrombosis. Its prothrombotic effects in vivo require TNFR2 and are partly compensated by TNFR1. In vitro studies indicate endothelial mechanisms to be responsible for prothrombotic TNFα effects. Our results support a more selective therapeutic approach in anticytokine therapy favouring TNFR2 specific antagonists.
Maternal Corticosterone Exposure in the Mouse Has Sex-Specific Effects on Placental Growth and mRNA Expression
Authors: Cuffe J. S. M. , O'Sullivan L. , Simmons D. G. , Anderson S. T. , Moritz K. M. 
Published: October 2012

Abstract
Maternal exposure to increased synthetic glucocorticoids (GC) during pregnancy is known to disturb fetal development and increase the risk of long-term disease. Maternal exposure to elevated levels of natural GC is likely to be common yet is relatively understudied. The placenta plays an important role in regulating fetal exposure to maternal GC but is itself vulnerable to maternal insults. This study uses a mouse model of maternal corticosterone (Cort) exposure to investigate its effects on the developing placenta. Mice were treated with Cort (33 μg/kg·h) for 60 h starting at embryonic d 12.5 (E12.5) before collection of placentas at E14.5 and E17.5. Although Cort exposure did not affect fetal size, placentas of male fetuses were larger at E17.5 in association with changes in placental Igf2. This increase in size was associated with an increase in placental thickness and an increase in placental junctional zone volume. Placentas from female fetuses were of normal size and had no changes in growth factor mRNA levels. The expression of the protective enzyme 11β-hydroxysteroid dehydrogenase type 2 was increased at E14.5 but was decreased in males at E17.5. In contrast, the expression of Nr3c1 (which encodes the GC receptor) was increased during the Cort exposure and remained elevated at E17.5 in the placentas of male fetuses. Our study has shown that maternal Cort exposure infers a sex-specific alteration to normal placental growth and growth factor expression, thus further adding to our understanding of the mechanisms of male dominance of programmed disease.
Calcium Signaling Regulates Trafficking of Familial Hypocalciuric Hypercalcemia (FHH) Mutants of the Calcium Sensing Receptor
Authors: Grant Michael P. , Stepanchick Ann , Breitwieser Gerda E. 
Published: October 2012

Abstract
Calcium-sensing receptors (CaSRs) regulate systemic Ca2+ homeostasis. Loss-of-function mutations cause familial benign hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT). FHH/NSHPT mutations can reduce trafficking of CaSRs to the plasma membrane. CaSR signaling is potentiated by agonist-driven anterograde CaSR trafficking, leading to a new steady state level of plasma membrane CaSR, which is maintained, with minimal functional desensitization, as long as extracellular Ca2+ is elevated. This requirement for CaSR signaling to drive CaSR trafficking to the plasma membrane led us to reconsider the mechanism(s) contributing to dysregulated trafficking of FHH/NSHPT mutants. We simultaneously monitored dynamic changes in plasma membrane levels of CaSR and intracellular Ca2+, using a chimeric CaSR construct, which allowed explicit tracking of plasma membrane levels of mutant or wild-type CaSRs in the presence of nonchimeric partners. Expression of mutants alone revealed severe defects in plasma membrane targeting and Ca2+ signaling, which were substantially rescued by coexpression with wild-type CaSR. Biasing toward heterodimerization of wild-type and FHH/NSHPT mutants revealed that intracellular Ca2+ oscillations were insufficient to rescue plasma membrane targeting. Coexpression of the nonfunctional mutant E297K with the truncation CaSRΔ868 robustly rescued trafficking and Ca2+ signaling, whereas coexpression of distinct FHH/NSHPT mutants rescued neither trafficking nor signaling. Our study suggests that rescue of FHH/NSHPT mutants requires a steady state intracellular Ca2+ response when extracellular Ca2+ is elevated and argues that Ca2+ signaling by wild-type CaSRs rescues FHH mutant trafficking to the plasma membrane.
Quantitative kinetics analysis of BMP2 uptake into cells and its modulation by BMP antagonists
Authors: Alborzinia Hamed , Schmidt-Glenewinkel Hannah , Ilkavets Iryna , Breitkopf-Heinlein Katja , Cheng Xinlai , Hortschansky Peter , Dooley Steven , Wölfl Stefan 
Published: October 2012

Summary
Bone morphogenetic proteins (BMPs) are members of the TGFβ family of signaling proteins and play an important role during development and in tissue formation. BMP signaling is a well-studied process, which is initiated through binding of cognate receptors and processed through activation of Smad downstream mediators. A hallmark of BMP signaling is its modulation at the extracellular level through specific antagonists. Although it had been shown that BMP and TGFβ receptors are internalized following activation, little is known about the fate of BMP ligands. We prepared biologically active fluorescently labeled BMP2 and quantitatively analyzed its binding and uptake in cells using flow cytometry and confocal microscopy. Exogenous BMP2 was rapidly bound to the cell surface and subsequently internalized in a time-dependent manner and accumulated in the cell center. Although binding to the cell surface was limited by binding sites at the beginning, internalization continously increased with time, after a short delay. Using different inhibitors we found that internalization of BMP2 through endosomal particles occurred in a clathrin-dependent pathway. Furthermore, uptake of BMP2 was modulated in strikingly different ways by BMP2 antagonists. Although Noggin and Gremlin increased BMP2 uptake, Chordin blocked BMP2 uptake, which was concentration dependent in both cases. In conclusion, our findings present interesting mechanisms for the modulation of BMP signaling by concentration gradients of BMP ligands and antagonists in a dose- and time-dependent manner, which can provide an explanation of some properties of the BMP regulatory network.
‘Poking’ microtubules bring about nuclear wriggling to position nuclei
Authors: Szikora Szilard , Gaspar Imre , Szabad Janos 
Published: October 2012

Summary
Nuclei wriggle in the cells of the follicle epithelium of the Drosophila pre-vitellogenic egg primordia. Although similar phenomena have been reported for a number of cultured cell types and some neurons in the zebrafish embryo, the mechanism and importance of the process have remained unexplained. Wriggling involves successive sudden and random minor turns of the nuclei, approximately three twists per minute with roughly 12° per twist, one of which lasts typically for 14 seconds. Wriggling is generated by the growing microtubules seeded throughout the cell cortex, which, while poking the nuclei, buckle and exert 5–40 piconewtons over ∼16 seconds. While wriggling, the nuclei drift ∼5 µm in a day in the immensely growing follicle cells along the apical–basal axis from the apical to the basal cell region. A &gt;2-fold excess of the microtubules nucleated in the apical cell region, as compared with those seeded in the basal cell cortex, makes the nuclei drift along the apical–basal axis. Nuclear wriggling and positioning appear to be tightly related processes: they cease simultaneously when the nuclei become anchored by the actin cytoskeleton; moreover, colchicine or taxol treatment eliminates both nuclear wriggling and positioning. We propose that the wriggling nuclei reveal a thus far undescribed nuclear positioning mechanism.
Antioxidant and molecular chaperone defenses during estivation and arousal in the South American apple-snailPomacea canaliculata
Authors: Giraud-Billoud Maximiliano , Vega Israel A. , Rinaldi Tosi Martín E. , Abud María A. , Calderón María L. , Castro-Vazquez Alfredo 
Published: October 2012

SummaryThe invasive Pomacea canaliculata estivates during periods of drought and should cope with harmful effects of reoxygenation during arousal. We studied thiobarbituric acid reactive substances (TBARS), enzymatic (superoxide dismutase, SOD and catalase, CAT) and non-enzymatic antioxidants (uric acid and reduced glutathione), and heat shock protein expression (Hsc70, Hsp70 and Hsp90) in (1) active control snails, (2) snails after 45 days of estivation, and (3) aroused snails 20 min and (4) 24 h after water exposure, in midgut gland, kidney and foot. Both kidney and foot (but not the midgut gland) showed a TBARS increase during estivation and a decrease after arousal. Tissue SOD and CAT did not change in any experimental groups. Uric acid increased during estivation in all tissues, and it decreased after arousal in the kidney. Allantoin, the oxidation product of uric acid, remained constant in the midgut gland but it decreased in the kidney until 20 min after arousal; however, allantoin levels rose in both kidney and foot 24 h after arousal. Reduced glutathione decreased during estivation and arousal, in both midgut gland and kidney, and it remained constant in the foot. Hsc70 and Hsp70 kidney levels were stable during the activity-estivation cycle and Hsp90 expression decrease during estivation and recovers in the early arousal. In foot, the expression of Hsp70 and Hsp90 was high during activity and estivation periods and diminished after arousal. Results indicate that a panoply of antioxidant and molecular chaperone defenses may be involved during the estivation-arousal cycle in this freshwater gastropod.
Humoral immune responses are maintained with age in a long-lived ectotherm, the red-eared slider turtle
Authors: Zimmerman Laura M. , Clairardin Sandrine G. , Paitz Ryan T. , Hicke Justin W. , LaMagdeleine Katie A. , Vogel Laura A. , Bowden Rachel M. 
Published: October 2012

Summary
Aging is typically associated with a decrease in immune function. However, aging does not affect each branch of the immune system equally. Because of these varying effects of age on immune responses, aging could affect taxa differently based on how the particular taxon employs its resources towards different components of immune defense. An example of this is found in the humoral immune system. Specific responses tend to decrease with age while non-specific, natural antibody responses increase with age. Compared with mammals, reptiles of all ages have a slower and less robust humoral immune system. Therefore, they may invest more in non-specific responses and thus avoid the negative consequences of age on the immune system. We examined how the humoral immune system of reptiles is affected by aging and investigated the roles of non-specific, natural antibody responses and specific responses by examining several characteristics of antibodies against lipopolysaccharide (LPS) in the red-eared slider turtle. We found very little evidence of immunosenesce in the humoral immune system of the red-eared slider turtle, which supports the idea that non-specific, natural antibody responses are an important line of defense in reptiles. Overall, this demonstrates that a taxon's immune strategy can influence how the immune system is affected by age.
Lobula-specific visual projection neurons are involved in perception of motion-defined second-order motion in Drosophila
Authors: Zhang Xiaonan , Liu He , Lei Zhengchang , Wu Zhihua , Guo Aike 
Published: October 2012

Summary
A wide variety of animal species including humans and fruit flies see second-order motion lacking coherent spatiotemporal correlations in luminance. Recent electrophysiological recordings, together with intensive psychophysical studies, are bringing to light the neural underpinnings of second-order motion perception in mammals. However, where and how the higher-order motion signals are processed in the fly brain is poorly understood. Using the rich genetic tools available in Drosophila and examining optomotor responses in fruit flies to several stimuli, we revealed that two lobula-specific visual projection neurons, specifically connecting the lobula and the central brain, are involved in the perception of motion-defined second-order motion, independent of whether the second-order feature is moving perpendicular or opposite to the local first-order motion. By contrast, blocking these neurons has no effect on first-order and flicker-defined second-order stimuli in terms of response delay. Our results suggest that visual neuropils deep in the optic lobe and the central brain, whose functional role in motion processing were previously unclear, may be specifically required for motion-defined motion processing.
The vestibuloocular reflex of tadpoles (Xenopus laevis) after knock-down of the isthmus related transcription factor XTcf-4
Authors: Horn Eberhard R. , El-Yamany Nabil A. , Gradl Dietmar 
Published: October 2012

SummaryDevelopment of the amphibian vestibular organ is regulated by molecular and neuronal mechanisms and by environmental input. The molecular component includes inductive signals derived from neural tissue of the hindbrain and from the surrounding mesoderm. The integrity of hindbrain patterning, on the other hand, depends on instructive signals from the isthmus organizer of the midbrain including the transcription factor XTcf-4. If the development of the vestibular system depends on the integrity of the isthmus as organizing centre, suppression of isthmus maintenance should modify vestibular morphology and function. We tested this hypothesis by down-regulation of the transcription factor XTcf-4. 10 pMol XTcf-4-specific antisense morpholino oligonucleotide were injected in one blastomere of 2-cell stage embryos of Xenopus laevis. For reconstitution experiments, 500 pg mRNA of the repressing XTcf-4A isoform or the activating XTcf-4C isoform were co-injected. Over-expression experiments were included using the same isoforms. Otoconia formation and vestibular controlled behaviour such as the roll-induced vestibuloocular reflex (rVOR) and swimming were recorded two weeks later. In 50% of tadpoles, down-regulation of XTcf-4 induced (1) a depression of otoconia formation accompanied by a reduction of the rVOR, (2) abnormal tail development, and (3) loop swimming behaviour. (4) All effects were rescued by co-injection of XTcf-4C but not or only partially by XTcf-4A. (5) Over-expression of XTcf-4A caused similar morphological and rVOR modifications as XTcf-4 depletion while over-expression of XTcf-4C had no effect. Because XTcf-4C has been described as essential factor for isthmus development, we postulate that the isthmus is strongly involved in vestibular development.
Shaking grounds, unearthing palimpsests: Semiotic anthropology of disaster
Authors: Morimoto, Ryo 
Published: October 2012

Abstract
This article will engage with the current disasters in Japan from the perspective of semiotic anthropology. Disaster seems to produce two moments of the sign: signa naturalia and signa data. The translation of the sign mirrors the architectonic of the signified of disaster, which is mediated by a token-level instantiation of signifiers that initially appears either absent or in excess. The conceptualization of disaster as a zero sign, that is, unlimited possibility, allows an investigation of “a struggle of interpretants” in stipulating the interpretative grounds of the signified amid regenerative processes of social regularity. It is this very exact moment of translation that the sustained continuity reveals its culture-specific “deep social grammar.” Disaster or “shaking grounds” has the presenting effect of cultural palimpsests. These unearthed palimpsests enable a heightened metasemiotic awareness of institutional and ideological regimentations, on the one hand, and token-level recontexualizations, assimilations, and hybridizations of the depository of signs in society in the post-disaster contexts, on the other. The article concludes with an attempt to synthesize Peircean semeiotics and Saussurean semiology by assessing the two distinct modes of semiosis, culture and trauma, upon a sudden threat of the experience of discontinuity.
NADPH Oxidase 1 Mediates α-Synucleinopathy in Parkinson's Disease
Authors: Cristóvão Ana Clara , Guhathakurta Subhrangshu , Bok Eugene , Je Goun , Yoo Seung Don , Choi Dong-Hee , Kim Yoon-Seong 
Published: October 2012

Accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson's disease (PD). Nevertheless, little is known about the mechanism contributing to α-synuclein aggregation and its further toxicity to dopaminergic neurons. Since oxidative stress can increase the expression and aggregation levels of α-synuclein, NADPH oxidases (Noxs), which are responsible for reactive oxygen species generation, could be major players in α-synucleinopathy. Previously, we demonstrated that Nox1 is expressed in dopaminergic neurons of the PD animal models as well as postmortem brain tissue of PD patients, and is responsible for oxidative stress and subsequent neuronal degeneration. Here, using paraquat (PQ)-basedin vitroandin vivoPD models, we show that Nox1 has a crucial role in modulating the behavior of α-synuclein expression and aggregation in dopaminergic neurons.We observed in differentiated human dopaminergic cells that Nox1 and α-synuclein expressions are increased under PQ exposure. Nox1 knockdown significantly reduced both α-synuclein expression and aggregation, supporting the role of Nox1 in this process. Furthermore, in rats exposed to PQ, the selective knockdown of Nox1 in the substantia nigra, using adeno-associated virus encoding Nox1-specific shRNA, largely attenuated the PQ-mediated increase of α-synuclein and ubiquitin expression levels as well as α-synuclein aggregates (proteinase K resistant) and A11 oligomers. Significant reductions in oxidative stress level and dopaminergic neuronal loss were also observed. Our data reveal a new mechanism by which α-synuclein becomes a neuropathologic protein through Nox1-mediated oxidative stress. This finding may be used to generate new therapeutic interventions that slower the rate of α-synuclein aggregation and the progression of PD pathogenesis.