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Years and Volumes

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Articles from this Volume

Hua Wang, Zhi-Hao Wang, Jing Kong,1 Meng-Yun Yang, Gui-Hua Jiang, Xu-Ping Wang, Ming Zhong, Yun Zhang, Jing-Ti Deng, and Wei Zhang

The fundamental mechanismsthat underlie platelet activation in atherothrombosis are still obscure. Oxidative stress is involved in central features of atherosclerosis. Platelet-derived microvesicles (PMVs) could be important mediators between oxidative stress and platelet activation. CD36 could be a receptor of PMVs, thus generating a PMV–CD36 complex. We aimed to investigate the detailed pathway by which oxidative damage contributes to platelet activation by the PMV–CD36 complex. We found that oxidized low-density lipoprotein stimulated the generation of PMVs. PMVs enhanced normal platelet activation, as assessed by the expression of integrin αIIbβ3, secretion of soluble P-selectin and platelet aggregation, but CD36-deficient platelets were not activated by PMVs. The function of the PMV–CD36 complex was mediated by the MKK4/JNK2 signaling axis. Meanwhile, PMVs increased the level of 8-iso-prostaglandin-F2α, a marker of oxidative stress, in a CD36- and phosphatidylserine-dependent manner. We concluded that PMVs are important mediators between oxidative stress and platelet activation. PMVs and CD36 may be effective targets for preventing platelet activation in cardiovascular diseases.

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Posted by Leah Caracappa on Apr 9, 2012 4:30 PM CDT
Rong Bu, Shahab Uddin, Maqbool Ahmed, Azhar R Hussain, Saif Alsobhi, Tarek Amin,
Abdurahman Al-Nuaim, Fouad Al-Dayel, Jehad Abubaker, Prashant Bavi, and Khawla S Al-Kuraya


The Met receptor tyrosine kinase is overexpressed and/or activated in variety of human malignancies. Previously we have shown that c-Met is overexpressed in Middle Eastern papillary thyroid carcinoma (PTC) and significantly associated with an aggressive phenotype, but its role has not been fully elucidated in PTC. The aim of this study was to determine the functional link between the c-Met/AKT signaling pathway and death receptor 5 (DR5) in a large cohort of PTC in a tissue microarray format followed by functional studies using PTC cell lines and nude mice. Our data showed that high expressions of p-Met and DR5 were significantly associated with an aggressive phenotype of PTC and correlated with BRAF mutation. Treatment of PTC cell lines with PHA665752, an inhibitor of c-Met tyrosine kinase, inhibited cell proliferation and induced apoptosis via the mitochondrial pathway in PTC cell lines. PHA665752 treatment or expression of c-Met small interfering (si)RNA resulted in dephosphorylation of c-Met, AKT and its downstream effector molecules. Furthermore, PHA665752 treatment upregulated DR5 expression via generation of reactive oxygen species in PTC cell lines, and synergistically potentiated death receptor–induced apoptosis with tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Finally, cotreatment with PHA665752 and TRAIL caused more pronounced effects on PTC xenograft tumor growth in nude mice. Our data suggest that the c-Met/AKT pathway may be a potential target for therapeutic intervention for treatment of PTC refractory to conventionally therapeutic modalities.

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Posted by Leah Caracappa on Apr 9, 2012 4:29 PM CDT
Alexandra M Nicholson, Lindsey A Wold, Dominic M Walsh, and Adriana Ferreira

Hereditary cerebral hemorrhage with amyloidosis–Dutch type is a disorder associated with a missense mutation (E693Q) in the β-amyloid (Aβ)-coding region of the amyloid precursor protein (APP). This familial disease is characterized by cognitive deficits secondary to intracerebral hemorrhage and, in some cases, progressive Alzheimer's disease (AD)-like dementia. Although this mutation was the first ever reported in the human APP gene, little is known about the molecular mechanisms underlying the direct toxic effects of this mutated Aβ on central neurons. In the present study, we assessed the role of calpain-mediated toxicity in such effects using an AD primary culture model system. Our results showed that Dutch mutant Aβ (E22Q) induced calpain-mediated cleavage of dynamin 1 and a significant decrease in synaptic contacts in mature hippocampal cultures. These synaptic deficits were similar to those induced by wild-type (WT) Aβ. In contrast, calpain-mediated tau cleavage leading to the generation of a 17-kDa neurotoxic fragment, as well as neuronal death, were significantly reduced in E22Q Aβ–treated neurons when compared with WT Aβ–treated ones. This complex regulation of the calpain-mediated toxicity pathway by E22Q Aβ could have some bearing in the pathobiology of this familial AD form.

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Posted by Leah Caracappa on Apr 9, 2012 4:27 PM CDT
Lei Qi, Xiaoxuan Cui, Weifeng Dong, Rafael Barrera, Jeffrey Nicastro, Gene F Coppa, Ping Wang, and Rongqian Wu

Traumatic brain injury (TBI) and hemorrhagic shock often occur concomitantly due to multiple injuries. Gastrointestinal dysfunction occurs frequently in patients with TBI. However, whether alterations in the gastrointestinal system are involved in modulating neuronal damage and recovery after TBI is largely neglected. Ghrelin is a "gut-brain" hormone with multiple functions including antiinflammation and antiapoptosis. The purpose of this study was to determine whether ghrelin attenuates brain injury in a rat model of TBI and uncontrolled hemorrhage (UH). To study this, brain injury was induced by dropping a 450-g weight from 1.5 m onto a steel helmet attached to the skull of male adult rats. Immediately after TBI, a midline laparotomy was performed and both lumbar veins were isolated and severed at the junction with the vena cava. At 45 min after TBI/UH, ghrelin (4, 8 or 16 nmol/rat) or 1 mL normal saline (vehicle) was intravenously administered. Brain levels of TNF-α and IL-6, and cleaved PARP-1 levels in the cortex were measured at 4 h after TBI/UH. Beam balance test, forelimb placing test and hindlimb placing test were used to assess sensorimotor and reflex function. In additional groups of animals, ghrelin (16 nmol/rat) or vehicle was subcutaneously (s.c.) administered daily for 10 d after TBI/UH. The animals were monitored for 28 d to record body weight changes, neurological severity scale and survival. Our results showed that ghrelin downregulated brain levels of TNF-α and IL-6, reduced cortical levels of cleaved PARP-1, improved sensorimotor and reflex functions, and decreased mortality after TBI/UH. Thus, ghrelin has a great potential to be further developed as an effective resuscitation approach for the trauma victims with brain injury and severe blood loss.

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Posted by Leah Caracappa on Apr 9, 2012 4:26 PM CDT
Teresina Laragione, Anish Shah, and Pércio S Gulko

Serum levels of vitamin D levels are commonly reduced in patients with rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. We recently identified a new vitamin D receptor transcriptional signature in synovial tissues from rats with mild and nonerosive arthritis, suggesting a vitamin D–mediated protective effect. In the present study, we address the hypothesis that part of the vitamin D protective effect is mediated via interference with fibroblast-like synoviocyte (FLS) invasive properties, an in vitro cellular phenotype that correlates with radiographic and histological damage in pristane-induced arthritis and RA. FLSs derived from DA rats with pristane- induced arthritis and RA patients were studied in an in vitro model of invasion through a collagen-rich barrier (Matrigel) over a 24-h period, in the presence or absence of calcitriol, an active form of vitamin D. Matrix metalloprotease (MMP) expression levels were analyzed with zymography and quantitative real-time polymerase chain reaction, and the cytoskeleton was studied with immunofluorescense microscopy. Calcitriol significantly inhibited DA and RA FLS invasion by 54% and 53%, respectively. Calcitriol also reduced interleukin (IL)-1β–induced expression of MMP-1 by 95% in DA FLSs and by 73.5% in RA FLS. Calcitriol treatment reduced actin cytoskeleton reorganization, reduced polarized formation of lamellipodia and reduced colocalization of phosphorylated focal adhesion kinase (p-FAK) with lamellipodia, all consistent with reduced cell ability to move and invade. In conclusion, we identified a new effect of calcitriol in FLS invasion. This discovery suggests that the reduced serum levels of vitamin D and its metabolites commonly seen in RA might increase risk for FLS-mediated cartilage and bone invasion and erosions. Treatment with vitamin D or its analogs has the potential to become a helpful adjuvant aimed at preventing or reducing joint destruction.

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Posted by Leah Caracappa on Apr 9, 2012 4:25 PM CDT
Lemeng Zhang, Jon S Cardinal, Runalia Bahar, John Evankovich, Hai Huang,1 Gary Nace,
Timothy R Billiar, Matthew R Rosengart, Pinhua Pan, and Allan Tsung


The pathogenesis of sepsis is complex and, unfortunately, poorly understood. The cellular process of autophagy is believed to play a protective role in sepsis; however, the mechanisms responsible for its regulation in this setting are ill defined. In the present study, interferon regulatory factor 1 (IRF-1) was found to regulate the autophagic response in lipopolysaccharide (LPS)-stimulated macrophages. In vivo, tissue macrophages obtained from LPS-stimulated IRF-1 knockout (KO) mice demonstrated increased autophagy and decreased apoptosis compared to those isolated from IRF-1 wild-type (WT) mice. In vitro, LPS-stimulated peritoneal macrophages obtained from IRF-1 KO mice experienced increased autophagy and decreased apoptosis. IRF-1 mediates the inhibition of autophagy by modulating the activation of the mammalian target of rapamycin (mTOR). LPS induced the activation of mTOR in WT peritoneal macrophages, but not in IRF-1 KO macrophages. In contrast, overexpression of IRF-1 alone increased the activation of mTOR and consequently decreased autophagic flux. Furthermore, the inhibitory effects of IRF-1 mTOR activity were mediated by nitric oxide (NO). Therefore, we propose a novel role for IRF-1 and NO in the regulation of macrophage autophagy during LPS stimulation in which IRF-1/NO inhibits autophagy through mTOR activation.

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Posted by Leah Caracappa on Apr 9, 2012 4:24 PM CDT
Bixi Jian, Shaolong Yang, Irshad H Chaudry, and Raghavan Raju

Mitochondria play a critical role in metabolic homeostasis of a cell. Our recent studies, based on the reported interrelationship between c-Myc and Sirt1 (mammalian orthologue of yeast sir2 [silent information regulator 2]) expression and their role in mitochondrial biogenesis and function, demonstrated a significant downregulation of Sirt1 protein expression and an upregulation of c-Myc following trauma-hemorrhage (T-H). Activators of Sirt1 are known to improve mitochondrial function and the naturally occurring polyphenol resveratrol (RSV) has been shown to significantly increase Sirt1 activity by increasing its affinity to both NAD+ and the acetylated substrate. In this study we tested the salutary effect of RSV following T-H and its influence on Sirt1 expression. Rats were subjected to T-H or sham operation. RSV (8 mg/kg body weight, intravenously) or vehicle was administered 10 min after the onset of resuscitation, and the rats were killed 2 h following resuscitation. Sirtinol, a Sirt1 inhibitor, was administered 5 min prior to RSV administration. Cardiac contractility (±dP/dt) was measured and heart tissue was tested for Sirt1, Pgc-1α, c-Myc, cytosolic cytochrome C expression and ATP level. Left ventricular function, after T-H, was improved (P < 0.05) following RSV treatment, with significantly elevated expression of Sirt1 (P < 0.05) and Pgc-1α (P < 0.05), and decreased c-Myc (P < 0.05). We also observed significantly higher cardiac ATP content, declined cytosolic cytochrome C and decreased plasma tumor necrosis factor-α in the T-H–RSV group. The salutary effect due to RSV was abolished by sirtinol, indicating a Sirt1-mediated effect. We conclude that RSV may be a useful adjunct to resuscitation fluid following T-H.

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Posted by Leah Caracappa on Apr 9, 2012 4:23 PM CDT
Hulda Sigridur Hreggvidsdóttir, Anna M Lundberg, Ann-Charlotte Aveberger, Lena Klevenvall, Ulf Andersson, and Helena Erlandsson Harris

The nuclear protein high mobility group box protein 1 (HMGB1) promotes inflammation upon extracellular release. HMGB1 induces proinflammatory cytokine production in macrophages via Toll-like receptor (TLR)-4 signaling in a redox-dependent fashion. Independent of its redox state and endogenous cytokine-inducing ability, HMGB1 can form highly immunostimulatory complexes by interaction with certain proinflammatory mediators. Such complexes have the ability to enhance the induced immune response up to 100-fold, compared with induction by the ligand alone. To clarify the mechanisms for these strong synergistic effects, we studied receptor requirements. Interleukin (IL)-6 production was assessed in supernatants from cultured peritoneal macrophages from mice each deficient in one of the HMGB1 receptors (receptor for advanced glycation end products [RAGE], TLR2 or TLR4) or from wild-type controls. The cultures were stimulated with the TLR4 ligand lipopolysaccaride (LPS), the TLR2 ligand Pam3CysSerLys4 (Pam3CSK4), noninflammatory HMGB1 or each TLR ligand in complex with noninflammatory HMGB1. The activity of the HMGB1-TLR ligand complexes relied on engagement of the same receptor as for the noncomplexed TLR ligand, since HMGB1-LPS complexes used TLR4 and HMGB1-Pam3CSK4 complexes used TLR2. Deletion of any of the intracellular adaptor molecules used by TLR2 (myeloid differentiation factor-88 [MyD88], TIR domain–containing adaptor protein [TIRAP]) or TLR4 (MyD88, TIRAP, TIR domain–containing adaptor-inducing interferon-β [TRIF], TRIF-related adaptor molecule [TRAM]) had similar effects on HMGB1 complex activation compared with noncomplexed LPS or Pam3CSK4. This result implies that the enhancing effects of HMGB1-partner molecule complexes are not regulated by the induction of additional signaling cascades. Elucidating HMGB1 receptor usage in processes where HMGB1 acts alone or in complex with other molecules is essential for the understanding of basic HMGB1 biology and for designing HMGB1-targeted therapies.

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Posted by Leah Caracappa on Apr 9, 2012 4:20 PM CDT
Cristina Nogueira-Silva, Emanuel Carvalho-Dias, Paulina Piairo, Susana Nunes, Maria J Baptista, Rute S Moura, and Jorge Correia-Pinto

Antenatal stimulation of lung growth is a reasonable approach to treat congenital diaphragmatic hernia (CDH), a disease characterized by pulmonary hypoplasia and hypertension. Several evidences from the literature demonstrated a possible involvement of renin-angiotensin system (RAS) during fetal lung development. Thus, the expression pattern of renin, angiotensin-converting enzyme, angiotensinogen, type 1 (AT1) and type 2 (AT2) receptors of angiotensin II (ANGII) was assessed by immunohistochemistry throughout gestation, whereas the function of RAS in the fetal lung was evaluated using fetal rat lung explants. These were morphometrically analyzed and intracellular pathway alterations assessed by Western blot. In nitrofen-induced CDH model, pregnant rats were treated with saline or PD-123319. In pups, lung growth, protein/DNA ratio, radial saccular count, epithelial differentiation and lung maturation, vascular morphometry, right ventricular hypertrophy and overload molecular markers, gasometry and survival time were evaluated. Results demonstrated that all RAS components were constitutively expressed in the lung during gestation and that ANGII had a stimulatory effect on lung branching, mediated by AT1 receptor, through p44/42 and Akt phosphorylation. This stimulatory effect on lung growth was mimicked by AT2-antagonist (PD-123319) treatment. In vivo antenatal PD-123319 treatment increased lung growth, ameliorated indirect parameters of pulmonary hypertension, improved lung function and survival time in nonventilated CDH pups, without maternal or fetal deleterious effects. Therefore, this study demonstrated a local and physiologically active RAS during lung morphogenesis. Moreover, selective inhibition of AT2 receptor is presented as a putative antenatal therapy for CDH.

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Posted by Leah Caracappa on Apr 9, 2012 4:17 PM CDT
Alexandra V Lucs, Rong Wu, Virginia Mullooly, Allan L Abramson, and Bettie M Steinberg

Recurrent respiratory papillomatosis (RRP) is caused by human papillomaviruses (HPVs), primarily types 6 and 11. The disease is characterized by multiple recurrences of airway papillomas, resulting in high levels of morbidity and significant mortality. The prevalence of latent HPV in the larynx of the general population is much greater than the prevalence of RRP, suggesting a host-susceptibility factor for disease. We report that the oncogene Rac1 and its downstream product cyclooxygenase-2 (COX-2) are both constitutively expressed at high levels throughout the airway of these patients, independent of active HPV infection. Use of the COX-2 inhibitor celecoxib in primary papilloma cell culture resulted in the downregulation of HPV transcription. Furthermore, a proof-of-principle study treating three patients with severe RRP with celecoxib resulted in remission of disease in all cases. Therefore, we have identified the first pharmacologically targetable host-susceptibility pathway that contributes to RRP recurrence.

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Posted by Leah Caracappa on Apr 9, 2012 4:12 PM CDT
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