Epoxyeicosatrienoic acid analog mitigates kidney injury in a rat model of radiation nephropathy
This study demonstrates a novel EET-analog based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis. (Source: Clinical Science)
Source: Clinical Science - January 21, 2016 Category: Biomedical Science Authors: Khan, M. A. H., Fish, B. L., Wahl, G., Sharma, A., Falck, J. R., Paudyal, M., Moulder, J. E., Imig, J. D., Cohen, E. P. Tags: PublishAheadOfPrint Source Type: research

PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homeostasis
Metabolic dysfunction is associated with adipose tissue inflammation and macrophage infiltration. The Platelet Activating Factor Receptor (PAFR) is expressed in several cell types and binds to PAF and oxidized phospholipids. Engagement of PAFR in macrophages drives them towards the anti-inflammatory phenotype. In the present study, we investigated whether genetic deficiency of PAFR affects the phenotype of adipose tissue macrophages (ATM) and its effect on glucose and insulin metabolism. PAFR-deficient (PAFRKO) and wild type mice (WT) were fed standard (SD) or high fat diet (HFD). Glucose and insulin tolerance tests were p...
Source: Clinical Science - January 19, 2016 Category: Biomedical Science Authors: Filgueiras, L. R., Koga, M. M., Quaresma, P. G., Ishizuka, E. K., Montes, M. B. A., Prada, P. O., Saad, M. J., Jancar, S., Rios, F. J. Tags: PublishAheadOfPrint Source Type: research

Epigenetic Regulation of Cyclooxygenase-2 by methylation of c8orf4 in Pulmonary Fibrosis.
Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis produce low levels of prostaglandin E2, due to a limited capacity to up-regulate cyclooxygenase-2. This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood.In the present study we examined whether the reduced level of cyclooxygenase-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5 Aza-2’-deoxycytidine restored cyclooxygenase-2 mRNA expression by fibrotic lung fibrobla...
Source: Clinical Science - January 7, 2016 Category: Biomedical Science Authors: Evans, I. C., Barnes, J. L., Garner, I. M., Pearce, D. R., Maher, T. M., Shi-wen, X., Renzoni, E. A., Wells, A. U., Denton, C. P., Laurent, G. J., Abraham, D. J., McAnulty, R. J. Tags: PublishAheadOfPrint Source Type: research

Role of matrix metalloproteinase (MMP)-9 in chronic kidney disease: a new biomarker of resistant albuminuria
Resistant albuminuria developed under adequate chronic renin-angiotensin system (RAS) blockade is a clinical problem present in a fraction of patients with chronic kidney disease (CKD). The mechanism underlying this resistant albuminuria remain unknown. Matrix metalloproteinases (MMPs) are involved in the pathophysiology of cardiovascular and renal disease. Here we tested the role of MMPs in resistant albuminuria. We first evaluated gelatinase MMP-2 and MMP-9 activity by zymography in the Munich Wistar Frömter (MWF) rat, a model of progressive albuminuria, and subsequently in patients with resistant albuminuria. Marke...
Source: Clinical Science - January 5, 2016 Category: Biomedical Science Authors: Pulido-Olmo, H., Garcia-prieto, C. F., Alvarez-llamas, G., Barderas, M. G., Vivanco, F., Aranguez, I., Somoza, B., Segura, J., Kreutz, R., Fernandez-Alfonso, M. S., Ruilope, L. M., Ruiz-Hurtado, G. Tags: PublishAheadOfPrint Source Type: research

Mechanism of vascular dysfunction due to circulating factors in women with preeclampsia
Circulating factors have been proposed to play a major role in the pathophysiology of endothelial dysfunction in preeclampsia (PE), which is defined as new-onset hypertension with proteinuria after 20 weeks of gestation. However, the mechanisms leading to altered vascular reactivity remain unclear. We hypothesized that circulating factors lead to endothelial dysfunction by increasing oxidative stress and reducing nitric oxide and prostaglandin bioavailability. Pregnant rat uterine and mesenteric arteries were incubated overnight with 3% normotensive (NP) or PE plasma collected from women upon admission to hospital. Respons...
Source: Clinical Science - January 5, 2016 Category: Biomedical Science Authors: Kao, C. K., Morton, J. S., Quon, A. L., Reyes, L. M., Lopez-jaramillo, P., Davidge, S. T. Tags: PublishAheadOfPrint Source Type: research

Human placenta-derived stromal cells decrease inflammation, placental injury, and blood pressure in hypertensive pregnant mice
Preeclampsia, the development of hypertension and proteinuria or end-organ damage during pregnancy, is a leading cause of both maternal and fetal morbidity and mortality and there are no effective clinical treatments for preeclampsia aside from delivery. The development of preeclampsia is characterized by maladaptation of the maternal immune system, excessive inflammation, and endothelial dysfunction. We have reported that detection of extracellular RNA by Toll-like receptors (TLRs) 3 and 7 is a key initiating signal that contributes to the development of preeclampsia. PLacental eXpanded (PLX-PAD; Pluristem Therapeutics, I...
Source: Clinical Science - December 18, 2015 Category: Biomedical Science Authors: Chatterjee, P., Chiasson, V. L., Pinzur, L., Raveh, S., Abraham, E., Jones, K. A., Bounds, K. R., Ofir, R., Flaishon, L., Chajut, A., Mitchell, B. M. Tags: PublishAheadOfPrint Source Type: research

Regulation of Amino Acid Transporter Trafficking by mTORC1 in Primary Human Trophoblast cells is Mediated by the Ubiquitin Ligase Nedd4-2.
In conclusion, we have identified a novel link between mTORC1 signaling and ubiquitination, a common posttranslational modification. Because placental mTORC1 is inhibited in fetal growth restriction and activated in fetal overgrowth, we propose that regulation of placental amino acid transporter ubiquitination by mTORC1 and Nedd4-2 constitutes a molecular mechanisms underlying abnormal fetal growth. (Source: Clinical Science)
Source: Clinical Science - November 25, 2015 Category: Biomedical Science Authors: Rosario, F. J., Dimasuay, K. G., Kanai, Y., Powell, T. L., Jansson, T. Tags: PublishAheadOfPrint Source Type: research

JAM-A promotes wound healing by enhancing both homing and secretion activities of mesenchymal stem cells
The homing ability and secretory function of mesenchymal stem cells (MSCs) are key factors that influence the cells’ involvement in wound repair. These factors are controlled by a multilayer regulatory circuitry, including adhesion molecules, core transcription factors (TFs), and certain other regulators. However, the role of adhesion molecules in this regulatory circuitry and their underlying mechanism remain undefined. Here, we demonstrate that an adhesion molecule, junction adhesion molecule A (JAM-A), may function as a key promoter molecule that regulates skin wound healing by MSCs. In in vivo experiments, we s...
Source: Clinical Science - May 21, 2015 Category: Biomedical Science Authors: M Wu, S Ji, S Xiao, Z Kong, H Fang, Y Zhang, K Ji, Y Zheng, H Liu, Z Xia Source Type: research

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin (1-7) through a p38 MAPK dependent mechanism
Skeletal muscle atrophy induced during sepsis syndrome produced by endotoxin as lipopolisaccharide (LPS), is a pathological condition characterized by the loss of strength and muscle mass, an increase in myosin heavy chain (MHC) degradation, and an increase in the expression of atrogin-1 and MuRF-1, two ubiquitin E3 ligases belonging to ubiquitin-proteasome system. Angiotensin (1-7) [Ang (1-7)], through its Mas receptor, produces beneficial effects in skeletal muscle. We evaluated in vivo the role of Ang (1-7) and Mas receptor on the muscle wasting induced by LPS injection to C57BL/10J mice. Studies in vitro were performed...
Source: Clinical Science - May 19, 2015 Category: Biomedical Science Authors: M Morales, H Olguin, G Di Capua, E Brandan, F Simon, C Cabello-Verrugio Source Type: research

Homocysteine facilitates LOX-1 activation and endothelial death through the PKC{beta} and SIRT1/HSF1 mechanism: relevance to human Hyperhomocysteinemia
Hyperhomocysteinemia (HHcy) is one of the major risk factors for cardiovascular diseases. A high concentration of Homocysteine (Hcy) induces endothelial dysfunction by activating endothelial oxidative stress. LOX-1 plays a vital role in regulating the progression of atherosclerotic lesions. LOX-1 activation causes endothelial apoptosis and inflammation. The mechanism is still unclear as to whether Hcy affects human endothelial LOX-1 expression. LOX-1 expression level was confirmed by Western blotting assay in Hcy-treated endothelial cells. L-methionine was used for HHct induction in animals. Our results suggested that Hcy ...
Source: Clinical Science - May 18, 2015 Category: Biomedical Science Authors: C Hung, S Chan, P Chu, K Tsai Source Type: research

Mineralocorticoid receptor blockade prevents vascular remodeling in a rodent model of type 2 diabetes mellitus
Mineralocorticoid receptors (MR), which are activated by mineralocorticoids and glucocorticoids, actively participate in mechanisms that affect the structure and function of blood vessels. Although experimental and clinical evidence shows that vascular damage in diabetes is associated with structural alterations in large and small arteries, the role of MR in this process needs further studies. Thus, we tested the hypothesis that MR,through redox-sensitive mechanisms, plays a role in diabetes-associated vascular remodeling. Male, 12-14 weeks-old db/db mice, a model of type 2 diabetes, and their non-diabetic counterpart cont...
Source: Clinical Science - May 13, 2015 Category: Biomedical Science Authors: M A B Silva, S B A Cau, R A M Lopes, C P Manzato, K B Neves, T B Nascimento, F L A C Mestriner, A C Montezano, A Nguyen Dinh Cat, R M Touyz, R C Tostes Source Type: research

Beta-Pro7Ang III is a novel highly selective angiotensn AT2 receptor agonist, which acts as a vasodepressor agent via the AT2 receptor in conscious SHR.
We have previously shown that individual b-amino acid substitution to Ang II reduced AT1R- but not AT2R-binding, and that the heptapeptide Ang III exhibited greater AT2R: AT1R selectivity than Ang II. Therefore, we hypothesised that β-amino acid substituted Ang III peptide analogues would yield highly selective AT2R ligands, which we have tested in binding and functional vascular assays. In competition binding experiments using either AT1R- or AT2R- transfected HEK-293 cells, novel β-substituted Ang III analogues lacked appreciable AT1R affinity while most compounds could fully displace [125I]-Sar1Ile8Ang II from...
Source: Clinical Science - May 8, 2015 Category: Biomedical Science Authors: M Del Borgo, Y Wang, S Bosnyak, M Khan, P Walters, I Spizzo, P Perlmutter, L Hilliard, K M Denton, M Aguilar, R E Widdop, E Jones Source Type: research

Age-associated modifications of intestinal permeability and innate immunity in human small intestine
The physical and immunological properties of the human intestinal epithelial barrier in ageing are largely unknown. Ileal biopsies from young (7-12 years), adult (20-40y) and ageing (67-77y) individuals not showing symptoms of gastrointestinal pathologies were used to assess levels of inflammatory cytokines, barrier integrity, and cytokine production in response to microbial challenges. Increased expression of IL-6, but not IFNg, TNF-a and IL-1b was observed during ageing; further analysis showed that CD11c+ dendritic cells (DCs) are one of the major sources of IL-6 in the ageing gut and expressed higher levels of CD40. Up...
Source: Clinical Science - May 7, 2015 Category: Biomedical Science Authors: A L. Man, E Bertelli, S Rentini, M Regoli, G Briars, M Marini, A J. M. Watson, C Nicoletti Source Type: research

Inhibition of the lymphocyte metabolic switch by the oxidative burst of human neutrophils
Activation of the phagocytic NADPH oxidase (NOX-2) in neutrophils is a critical process in the innate immune system and is associated with elevated local concentrations of superoxide, hydrogen peroxide and hypochlorous acid. Under pathological conditions, NOX-2 activity has been implicated in the development of autoimmunity, indicating a role in modulating lymphocyte effector function. Notably, T cell clonal expansion and subsequent cytokine production requires a metabolic switch from mitochondrial respiration to aerobic glycolysis. Previous studies demonstrate that hydrogen peroxide generated from activated neutrophils su...
Source: Clinical Science - May 7, 2015 Category: Biomedical Science Authors: P A Kramer, L Prichard, B Chacko, S Ravi, E Turner Overton, S L Heath, V Darley-Usmar Source Type: research

Rosuvastatin improves hepatopulmonary syndrome through inhibition of inflammatory angiogenesis of lung
The hepatopulmonary syndrome (HPS) is characterized by hypoxia and increased intrapulmonary shunts in cirrhotic patients. Emerging evidences showed promising results of treating HPS by abolishment of intrapulmonary inflammation and angiogenesis. Rosuvastatin is a kind of 3-hydroxy-methyl-3-glutamyl coenzyme A reductase inhibitor. In addition to lipid-lowering effect, it owns capacities of anti-inflammation and anti-angiogenesis. We postulated that rosuvastatin treatments can ameliorate HPS. Common bile duct ligation (CBDL) was applied as an experimental HPS animal model. CBDL rats received 2-week rosuvastatin (20 mg/kg/day...
Source: Clinical Science - May 5, 2015 Category: Biomedical Science Authors: C Chang, S Wang, H Hsieh, W Lee, C Chuang, H Lin, F Lee, S Lee, H Huang Source Type: research

Interleukin-34 {-} a new modulator of human and experimental inflammatory bowel disease
Inflammatory bowel diseases (IBD), where Crohn’s disease (CD) and ulcerative colitis (UC) represent the two main forms, are chronic inflammatory conditions of the intestine. Macrophages play a central role for IBD pathogenesis and are regulated by major differentiation factors such as colony-stimulating factor 1 (CSF-1) in homeostasis and inflammation. Interleukin (IL)-34 has recently been discovered as a second ligand for the CSF-1 receptor (CSF-1R). However, expression and involvement of IL-34 in IBD remain unknown. Here, we investigated the expression of IL34, CSF1, and their shared receptor CSF1R in normal human ...
Source: Clinical Science - April 21, 2015 Category: Biomedical Science Authors: S Zwicker, G Lago Martinez, M Bosma, M Gerling, R Clark, M Majster, J Söderman, S Almer, E Almer Boström Source Type: research

Metabolic dysfunction in lymphocytes promotes postoperative morbidity.
Perioperative lymphopenia has been linked with an increased risk of postoperative infectious complications, but the mechanisms remain unclear. We tested the hypothesis that bioenergetic dysfunction is an important mechanism underlying lymphopaenia, impaired functionality and infectious complications. In two cohorts of patients (61-82 years old) undergoing orthopaedic joint replacement (n=417, 328, respectively), we confirmed prospectively that preoperative lymphopaenia (≤1.3 x 109.L-1;
Source: Clinical Science - April 20, 2015 Category: Biomedical Science Authors: M R Edwards, P Sultan, A Gutierrez Del Arroyo, J Whittle, S N Karmali, S Moonesinghe, F S Haddad, M G Mythen, M Singer, G Lewis Ackland Source Type: research

Placental DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha promoter is associated with maternal gestational glucose level
Conclusions: Epigenetic alteration in PPAGRC1A promoter may be one of the potential mechanisms underlying the metabolic programming in offspring exposed to intrauterine hyperglycemia. (Source: Clinical Science)
Source: Clinical Science - April 15, 2015 Category: Biomedical Science Authors: X Xie, H Gao, W Zeng, S Chen, L Feng, D Deng, F Qiao, L Liao, K McCormick, Q Ning, X Luo Source Type: research

IL-35 inhibits HBV antigen-specific IFN-{gamma}-producing CTLs in vitro
In this study, we investigatedwhether interleukin-35 is involved in HBV-related cellular immune responses. CD4+ T-cells from peripheral blood were derived from healthy volunteers, resolved HBV individuals and chronic active hepatitis B patients and stimulated with CD3/28-conjugated beads. We analyzed mRNA and protein levels of interleukin-35, and assessed the inhibitory effect of interleukin-35 on HBV core antigen specific cytotoxic T lymphocytes, dendritic cells, and effector T-cells. Correlation analyses between liver inflammation and HBV DNA load were conducted. Results show thatchronic HBV patients harbor significantly...
Source: Clinical Science - April 14, 2015 Category: Biomedical Science Authors: X Li, L Tian, Y Dong, Q Zhu, Y Wang, W Han, X Liu, Q Ni, Y Chen, L Li Source Type: research

Serum proprotein convertase subtilisin/kexin type 9 concentration is not increased by plant stanol ester consumption in normo- to moderately hypercholesterolemic non-obese subjects. The Blood Flow intervention study
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL cholesterol metabolism by targeting LDL receptors for degradation. Statins increase serum PCSK9 concentration limiting the potential of statins to reduce LDL cholesterol, whereas ezetimibe, inhibitor of cholesterol absorption, has ambiguous effects on circulating PCSK9 levels. Plant stanols also reduce cholesterol absorption, but their effect on serum PCSK9 concentration is not known. Therefore, we performed a controlled, randomized, double-blind study, in which 92 normo- to moderately hypercholesterolemic subjects (35 males and 57 females) consumed vegeta...
Source: Clinical Science - April 10, 2015 Category: Biomedical Science Authors: P Simonen, U Stenman, H Gylling Source Type: research

Diverging biological roles among human monocyte subsets in the context of tuberculosis infection
Circulating monocytes (Mo) play an essential role in the host immune response to chronic infections. We previously demonstrated that CD16pos Mo were expanded in Tuberculosis (TB) patients, correlated with disease severity and were refractory to dendritic cell differentiation. Here, we investigated whether human Mo subsets (CD16neg and CD16pos) differed in their ability to influence the early inflammatory response against Mycobacterium tuberculosis (Mtb). We first evaluated the capacity of the Mo subsets to migrate and engage a microbicidal response in vitro. Accordingly, CD16neg Mo were more prone to migrate in response to...
Source: Clinical Science - April 10, 2015 Category: Biomedical Science Authors: L Balboa, J Barrios-payan, E González-domínguez, C Lastrucci, G Lugo-villarino, D Mata-espinoza, P Schierloh, D Kviatcovsky, O Neyrolles, I Maridonneau-parini, C Sánchez-torres, M del Carmen Sasiain, R Hernández-pando Source Type: research

Glucocorticoids suppress GLP-1 secretion: possible contribution to their diabetogenic effects
Evidence indicates that subtle abnormalities in glucocorticoid (GC) plasma concentrations and/or in tissue sensitivity to GCs are important in the metabolic syndrome, and it is generally agreed that GCs induce insulin resistance. In addition, it was recently reported that short-term exposure to GCs reduced the insulinotropic effects of the incretin glucagon-like peptide-1 (GLP-1). However, while defective GLP-1 secretion has been correlated to insulin resistance, potential direct effects of GCs on GLP-1-producing L-cell function in terms of GLP-1 secretion and apoptosis have not been studied in any greater detail. In the p...
Source: Clinical Science - April 8, 2015 Category: Biomedical Science Authors: C Kappe, L Fransson, P Wolbert, H Ortsäter Source Type: research

Short-term dietary salt supplementation blunts telmisartan induced increases in plasma renin activity in hypertensive patients with type 2 diabetes mellitus
Current guidelines recommend low dietary salt intake in patients with diabetes to reduce blood pressure. However, low salt intake has been associated with higher mortality rates in people with diabetes. Our aim is to examine the effect of angiotensin II receptor blocker (ARB), telmisartan, with and without dietary sodium chloride (NaCl) supplementation, on blood pressure (mean arterial pressure, MAP), plasma renin activity (PRA), serum aldosterone level and estimated glomerular filtration rate (eGFR) in hypertensive patients with type 2 diabetes. In a randomised, double blind, controlled study (RCT), 28 patients with ty...
Source: Clinical Science - April 7, 2015 Category: Biomedical Science Authors: A Xun-Nan Chen, G Jerums, S Baqar, E Annie Lambert, G Somarajah, G Thomas, C O'Callaghan, R J MacIsaac, E Ekinci Source Type: research

Inhibition of PKC{beta}2 Overexpression Ameliorates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats via Restoring Caveolin-3/Akt Signaling
Activation of Protein Kinase Cβ (PKCβ) plays a critical role in myocardial ischemia/reperfusion (I/R) injury in non-diabetic rodents. In the myocardium of diabetes, PKCβ2 is overexpressed that is associated with increased vulnerability to post-ischemic I/R injury with concomitantly impaired cardiomyocyte caveolin (Cav)-3 and Akt signaling as compared with non- diabetic rats. We hypothesized that myocardial PKCβ overexpression in diabetes exacerbates myocardial I/R injury through impairing Cav-3/Akt signaling. Streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor ruboxi...
Source: Clinical Science - April 7, 2015 Category: Biomedical Science Authors: Y Liu, J Jin, S Qiao, S Lei, S Liao, Z Ge, H Li, G Tin-chun Wong, M G Irwin, Z Xia Source Type: research

Lactate kinetics and mitochondrial respiration in skeletal muscle of healthy humans under influence of adrenaline
In conclusion a 3-compartment model gives additional information to the 2-compartment model but due to its larger variation and invasive muscle biopsy it is less likely to become a regularly used tool in clinical research. Hyperlactatemia in response to adrenergic stimuli was driven by an elevated lactate release from skeletal muscle most likely due to a redirection of a high intramuscular turnover rather than an increased production. (Source: Clinical Science)
Source: Clinical Science - April 1, 2015 Category: Biomedical Science Authors: J Grip, T Jakobsson, C Hebert, M Klaude, G Sandström, J Wernerman, O Rooyackers Source Type: research

Effects of Normoxic and Hypoxic Exercise Regimens on Monocyte-mediated Thrombin Generation in Sedentary Men
This study explores the manner in which normoxic and hypoxic exercise regimens affect procoagulant monocyte-derived microparticle (MDMP) formation and monocyte-promoted thrombin generation (TG).Forty sedentary healthy males were randomized to perform either normoxic (NET; 21%O2, n=20) or hypoxic (HET; 15%O2, n=20) exercise training (60%VO2max) for 30 min/day, 5 days/week for 5 weeks. At rest and immediately after hypoxic exercise test (HE, 100W under 12%O2 for 30 min), the MDMP characteristics and dynamic TG were measured by flow cytometry and thrombinography, respectively.The results demonstrated that acute 12%O2 exercise...
Source: Clinical Science - March 31, 2015 Category: Biomedical Science Authors: J Wang, Y Chang, Y Chen, H Tsai, T Fu Source Type: research

Interleukin-34 sustains inflammatory pathways in the gut
In conclusion, data indicate that IL-34 is up-regulated in IBD and suggest a role for this cytokine in sustaining the inflammatory responses in this disease. (Source: Clinical Science)
Source: Clinical Science - March 24, 2015 Category: Biomedical Science Authors: E Franzè, I Monteleone, M Cupi, P Mancia, F Caprioli, I Marafini, A Colantoni, A Ortenzi, F Laudisi, G Sica, P Sileri, F Pallone, G Monteleone Source Type: research

SRY Gene Transferred by Extracellular Vesicles Accelerates Atherosclerosis by Promotion of Leukocyte Adherence to Endothelial Cells
To study if and how SRY (sex determining region, Y) DNAs in plasma extracellular vesicle (EVs) is involved in the pathogenesis of atherosclerosis. PCR and gene sequencing found SRY gene fragment in plasma EVs from male but not from female patients; EVs from male patients with coronary artery disease (CAD) had higher SRY gene copy number (GCN) than healthy subjects. Additional studies found that leukocytes, the major source of plasma EVs, had higher SRY GCN and mRNA and protein expression in male CAD patients than controls. After incubation with EVs from SRY-transfected HEK293 cells, monocytes (THP-1) and endothelial cells ...
Source: Clinical Science - March 18, 2015 Category: Biomedical Science Authors: J Cai, W Guan, X Tan, C Chen, L Li, N Wang, X Zou, F Zhou, J Wang, F Pei, X Chen, H Luo, X Wang, D He, L Zhou, P A. Jose, C Zeng Source Type: research

A short term mouse model that reproduces the immunopathological features of rhinovirus induced exacerbation of COPD
Viral exacerbations of chronic obstructive pulmonary disease (COPD), commonly caused by rhinovirus (RV) infection, are poorly controlled by current therapies. This is due to a lack of understanding of the underlying immunopathological mechanisms. Human studies have identified a number of key immune responses that are associated with RV-induced exacerbations including neutrophilic inflammation, expression of inflammatory cytokines and deficiencies in innate anti-viral interferon. Animal models of COPD exacerbation are required to determine the contribution of these responses to disease pathogenesis. We aimed to develop a sh...
Source: Clinical Science - March 18, 2015 Category: Biomedical Science Authors: A Singanayagam, N Glanville, R P Walton, J Aniscenko, R M Pearson, J W Pinkerton, J C Horvat, P M Hansbro, N W Bartlett, S L Johnston Source Type: research

Toll-like receptor 5 deficiency exacerbates cardiac injury and inflammation induced by myocardial ischemia-reperfusion in the mouse
Myocardial ischemia-reperfusion (MIR) triggers a sterile inflammatory response important for myocardial healing, but which may also contribute to adverse ventricular remodeling. Such inflammation is initiated by molecular danger signals released by damaged myocardium, which induce innate immune responses by activating toll-like receptors (TLRs). Detrimental roles have been recently reported for TLR2, TLR3 and TLR4. The role of other TLRs is unknown. We therefore evaluated the role of TLR5, expressed at high level in the heart, in the development of myocardial damage and inflammation acutely triggered by MIR. TLR5-/- and wi...
Source: Clinical Science - March 11, 2015 Category: Biomedical Science Authors: R Parapanov, J Lugrin, N Rosenblatt-Velin, F Feihl, B Waeber, G Milano, C Vergely, N Li, P Pacher, L Liaudet Source Type: research

Folic acid supplementation improves microvascular function in aged humans through nitric oxide-dependent mechanisms
Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilation. Folic acid and its metabolite 5-methyltetrahydrofolate (5-MTHF) are reported to improve vessel function. We hypothesized that (1) local 5-MTHF administration, and (2) chronic folic acid supplementation would improve cutaneous microvascular function in aging through NO-dependent mechanisms. Eleven young (Y:22±1yrs) and 11 older (O:71±3yrs) subjects participated in 2 separate studies. In both studies, two intradermal microdialysis fibers were placed in the forearm skin for local d...
Source: Clinical Science - March 9, 2015 Category: Biomedical Science Authors: A E Stanhewicz, L M Alexander, W Kenney Source Type: research

Mindin regulates vascular smooth muscle cell phenotype and prevents neointima formation
Mindin/spondin 2, an extracellular matrix (ECM) component that belongs to the thrombospondin type 1 (TSR) class of molecules, plays prominent roles in the regulation of inflammatory responses, angiogenesis and metabolic disorders. Our most recent studies indicated that mindin is largely involved in the initiation and development of cardiac and cerebrovascular diseases. However, the regulatory functions of mindin in neointima formation remain unclear. In the present study, mindin expressions were significantly downregulated in platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) and wi...
Source: Clinical Science - March 9, 2015 Category: Biomedical Science Authors: L Zhu, L Huang, X Zhang, P Zhang, S Zhang, H Guan, Y Zhang, X Zhu, S Tian, K Deng, H Li Source Type: research

Hemolytic Uremic Syndrome is associated with dysregulation of Chemokine Receptor expression in Circulating Monocytes.
Conclusions: The increase in CCRs expression correlates with HUS severity suggesting that the dysregulation of these receptors might contributes to an increased risk for renal damage. Activated Mo could be recruited by chemokines and then receptors could be dysregulated. The dysregulation of CCRs and their ligands observed during acute period suggest that chemokine pathway would participate in HUS development. (Source: Clinical Science)
Source: Clinical Science - March 6, 2015 Category: Biomedical Science Authors: M Ramos, M Ruggieri, A Cecilia Panek, M Pilar Mejias, R Jimena Fernandez-brando, M Jimena Abrey-Recalde, A Exeni, C Barilari, R Exeni, M Sandra Palermo Source Type: research

Basic fibroblast growth factor induces VEGF expression in chondrosarcoma cells and subsequently promotes endothelial progenitor cells-primed angiogenesis
Chondrosarcoma, a common malignant tumor, develops in bone. Effective adjuvant therapy remains inadequate for treatment, meaning poor prognosis. It is imperative to explore novel remedies. Angiogenesis is a rate-limiting step in progression that explains neovessel formation for blood supply in tumor microenvironment. Numerous studies indicate endothelial progenitor cells (EPCs) promoting angiogenesis and contributing to tumor growth. Basic fibroblast growth factor (bFGF), a secreted cytokine, regulates biological activity including angiogenesis and correlates with tumorigenesis. However, the role of bFGF in angiogenesis-re...
Source: Clinical Science - March 4, 2015 Category: Biomedical Science Authors: H Tzeng, P Chen, K Lin, C Lin, C Tsai, S Han, C Teng, W Hwang, S Wang, C Tang Source Type: research

Breaking up of prolonged sitting over three days sustains, but does not enhance, lowering of postprandial plasma glucose and insulin in overweight and obese adults
Conclusion: There were significant between-condition effects but no temporal change in metabolic responses to MTT, indicating that breaking up sitting over three days sustains, but does not enhance, the lowering of postprandial glucose and insulin. (Source: Clinical Science)
Source: Clinical Science - March 3, 2015 Category: Biomedical Science Authors: R N Larsen, B A Kingwell, C Robinson, L Hammond, E Cerin, J E Shaw, G N Healy, M T Hamilton, N Owen, D W Dunstan Source Type: research

Nitroxyl: a vasodilator of human vessels that is not susceptible to tolerance
This study explores the efficacy of HNO in human blood vessels and describes, for the first time, a vasodilator for humans that is not susceptible to tolerance. Human radial arteries and saphenous veins were obtained from patients undergoing coronary artery graft surgery and mounted in organ baths. Repeated vasodilator responses to the HNO donor, Angeli’s salt (AS), and NO• donor, glyceryl trinitrate (GTN) were determined. AS and GTN induced concentration-dependent vasorelaxation of both human radial arteries (AS pEC50: 6.5±0.2 –log M) and saphenous veins (pEC50: 6.7±0.1 –log M) with si...
Source: Clinical Science - March 2, 2015 Category: Biomedical Science Authors: K L Andrews, N G Lumsden, J Farry, A Jefferis, B K Kemp-Harper, J P F Chin-Dusting Source Type: research

The role of miR-31/FIH1 pathway in TGF{beta}-induced liver fibrosis
In conclusion, miR-31/FIH1 pathway associates with liver fibrosis, perhaps by participating TGFβ/Smad3 signaling in HSC. (Source: Clinical Science)
Source: Clinical Science - March 2, 2015 Category: Biomedical Science Authors: J Hu, C Chen, Q Liu, B Liu, C Song, S Zhu, C Wu, S Liu, H Yu, D Yao, J Kang, L Zhu Source Type: research

{Soft hyphen}{Soft hyphen}{Soft hyphen}Neurogenic Hyperadrenergic Orthostatic Hypotension {-} A Newly-recognized Variant of Orthostatic Hypotension in Older Adults with Elevated Norepinephrine
We report a subset of patients who clinically have typical neurogenic OH but who paradoxically have elevated upright levels of plasma norepinephrine. We retrospectively studied 83 OH patients evaluated at the Vanderbilt Autonomic Dysfunction Center between August 2007 and May 2013. Based upon standing norepinephrine, patients were dichotomized into a hyperadrenergic orthostatic hypotension group (hyperOH: upright NE ≥3.55 nmol/L [600 pg/mL], n=19) or a non-hyperadrenergic orthostatic hypotension group (nOH: upright NE
Source: Clinical Science - February 23, 2015 Category: Biomedical Science Authors: P L Mar, C A Shibao, E M Garland, B K Black, I Biaggioni, A Diedrich, S Y Paranjape, D Robertson, S R Raj Source Type: research

Impact of Transient Hypotension on Regional Cerebral Blood Flow in Humans
We examined the impact of progressive hypotension with and without hypocapnia on regional extracranial cerebral blood flow and intra-cranial velocities. Participants underwent progressive lower-body negative pressure until pre-syncope to inflict hypotension. End-tidal carbon dioxide was clamped at baseline levels (isocapnic trial) or uncontrolled (poikilocapnic trial). Middle and posterior cerebral artery blood velocities (transcranial Doppler), heart rate, blood pressure and end-tidal carbon dioxide were obtained continuously. Measurements of internal carotid artery and vertebral artery blood flow were also obtained. Over...
Source: Clinical Science - February 20, 2015 Category: Biomedical Science Authors: N CS Lewis, K J Smith, A R Bain, K W Wildfong, T Numan, P N Ainslie Source Type: research

Pigment epithelium-derived factor regulates microvascular permeability through adipose triglyceride lipase in sepsis
The integrity of the vascular barrier, which is essential to blood vessel homeostasis, can be disrupted by a variety of soluble permeability factors during sepsis. Pigment epithelium-derived factor (PEDF), a potent endogenous anti-angiogenic molecule, is significantly increased in sepsis, but its role in endothelial dysfunction has not been defined. To assess the role of PEDF in the vasculature, we evaluated the effects of exogenous PEDF in vivo using a mouse model of cecal ligation and puncture (CLP)-induced sepsis and in vitro using human dermal microvascular endothelial cells (HDMECs). In addition, PEDF was inhibited us...
Source: Clinical Science - February 20, 2015 Category: Biomedical Science Authors: T He, J Hu, G Yan, L Li, D Zhang, Q Zhang, B Chen, Y Huang Source Type: research

T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis
In this study we investigated the generation of different Th responses by human dendritic cells (DCs) in MS. We compared the production of several Th cytokines by naive CD4 T cells polarized with myeloid and plasmacytoid dendritic cells (mDCs and pDCs) in healthy donors and relapsing-remitting (RR) MS patients. We found that resiquimod-stimulated mDCs were able to activate Th17 differentiation, while pDCs induced interleukin (IL)-10-producing Th cells. Surprisingly, resiquimod-stimulated pDCs from MS patients also significantly induced the differentiation of Th9 cells, which produce IL-9 and are known to be involved in all...
Source: Clinical Science - February 20, 2015 Category: Biomedical Science Authors: G Ruocco, S Rossi, C Motta, G Macchiarulo, F Barbieri, M De Bardi, G Borsellino, A Finardi, M Grasso, S Ruggieri, C Gasperini, R Furlan, D Centonze, L Battistini, E Volpe Source Type: research

Testosterone induces leukocyte migration by NADPH oxidase-driven ROS- and COX2-dependent mechanisms
The mechanisms whereby testosterone increases cardiovascular risk are not clarified. However, oxidative stress and inflammation seem to be determinant. Herein, we sought to determine whether exogenous testosterone, in physiological levels, induces leukocyte migration, a central feature in immune and inflammatory responses, and the mediating mechanisms. We hypothesized that testosterone induces leukocyte migration via NADPH oxidase (NADPHox)-driven reactive oxygen species and cyclooxygenase-dependent mechanisms. Sixteen week-old Wistar rats received an intraperitoneal injection (5 mL) of either testosterone (10-7 mol/L) or ...
Source: Clinical Science - February 20, 2015 Category: Biomedical Science Authors: A Z Chignalia, M Oliveira, V Debbas, R O. Dull, F R. M. Laurindo, R M Touyz, M C Carvalho, Z B Fortes, R C Tostes Source Type: research

The serum protein fetuin-B is involved in the development of acute myocardial infarction
This study may provide a therapeutic advantage for patients at high risk of AMI. (Source: Clinical Science)
Source: Clinical Science - February 11, 2015 Category: Biomedical Science Authors: S Jung, K Won, K Lee, H Kim, E Seo, H Lee, E Park, S Lee, B Kim Source Type: research

Hypotensive and sympathoinhibitory responses to selective central AT2 receptor stimulation in spontaneously hypertensive rats
The type 2 angiotensin (AT2) receptor has been suggested to counterbalance the type 1 angiotensin (AT1) receptor in the central regulation of blood pressure and sympathetic tone. We here investigated the blood pressure responses to stimulation of central AT2 receptors by the selective agonist Compound 21 in conscious SHR and normotensive WKY rats. We also assessed the impact on norepinephrine plasma levels, autonomic function, spontaneous baroreflex sensitivity, and the possible involvement of the nitric oxide-pathway and the AT1 receptor. Chronic intracerebroventricular Compound 21 infusion lowered blood pressure and nor...
Source: Clinical Science - February 6, 2015 Category: Biomedical Science Authors: S Brouwers, I Smolders, R D Wainford, A G Dupont Source Type: research

Vinexin-{beta} Exacerbates Cardiac Dysfunction Post-Myocardial Infarction via Mediating Apoptotic and Inflammatory Responses
In this study, dramatically upregulated Vinexin-β expressions were observed in both the ischemic human hearts and infarcted animal hearts. To further explore the potential involvement of Vinexin-β in MI, we induced MI injury in global Vinexin-β knockout (KO) mice and wild-type (WT) controls as well as mice with cardiac-specific overexpression of the human Vinexin-β gene (TG) and non-transgenic (NTG) littermates. Compared with that observed in WT controls, Vinexin-β deficiency significantly decreased MI-induced infarct size, concomitant with an improvement in cardiac function, leading to an increase...
Source: Clinical Science - February 6, 2015 Category: Biomedical Science Authors: X Liu, N Wan, X Zhang, Y Zhao, Y Zhang, G Hu, F Wan, R Zhang, X Zhu, H Xia, H Li Source Type: research

Circulating PCSK9 levels are positively correlated with NMR-assessed atherogenic dyslipidemia in patients with high cardiovascular risk
Background: The PCSK9 gene regulates cholesterol homeostasis by accelerating LDLR degradation resulting in the decreased catabolism of LDL leading to hypercholesterolemia. PCSK9 has also been related to other metabolic risk factors such as triglycerides and glucose levels and body mass index. Therefore, our aim was to study the relationship between PCSK9 and the lipid and lipoprotein profile. Methods: We studied 267 diabetic and metabolic syndrome patients who were not receiving any lipid-lowering therapy. We measured circulating lipids, cholesterol in remnant lipoproteins (RLPc) and PCSK9 levels. A detailed lipoprotein pr...
Source: Clinical Science - February 4, 2015 Category: Biomedical Science Authors: M Guardiola, N Plana, D Ibarretxe, A Cabré, M González, J Ribalta, L Masana Source Type: research

Quadriceps muscle weakness and atrophy are associated with a differential Epigenetic Profile in Advanced COPD
Epigenetic mechanisms regulate muscle mass and function in models of muscle dysfunction and atrophy. We assessed whether quadriceps muscle weakness and atrophy are associated with a differential expression profile of epigenetic events in patients with advanced COPD. In vastus lateralis (VL) of sedentary severe COPD patients (n=41), who were further subdivided into those with (n=25) and without (n=16) muscle weakness, and healthy controls (n=19), expression of muscle-enriched microRNAs, histone acetyltransferases (HATs) and deacetylases (HDACs), growth and atrophy signaling markers, total protein and histone acetylation, tr...
Source: Clinical Science - January 28, 2015 Category: Biomedical Science Authors: E Puig-Vilanova, J Martinez-Llorens, P Ausin, J Roca, J Gea, E Barreiro Source Type: research

Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte
Minimal change nephropathy (MCN) is the third most common cause of primary nephrotic syndrome in adults. Most patients with MCN respond to corticosteroid therapy, but relapse is common. In children, steroid-dependent patients are often given alternative agents to spare the use of steroids and to avoid the cumulative steroid toxicity. In this respect, levamisole has shown promise due to its ability to effectively maintain remission in children with steroid-sensitive or steroid-dependent nephrotic syndrome. Despite clinical effectiveness, there is a complete lack of molecular evidence to explain its mode of action and there ...
Source: Clinical Science - January 27, 2015 Category: Biomedical Science Authors: L Jiang, I Dasgupta, J A Hurcombe, H F Colyer, P W Mathieson, G I Welsh Source Type: research

Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression
Complex I (CI) is the largest of the five multi-subunit complexes constituting the human oxidative phosphorylation (OXPHOS) system. Seven of its catalytic core subunits are encoded by mitochondrial DNA (ND1-ND6, ND4L), with mutations in all seven having been reported in association with isolated CI deficiency. We investigated two unrelated adult patients presenting with marked exercise intolerance, persistent lactic acidaemia and severe, muscle-restricted isolated CI deficiency associated with subsarcolemmal mitochondrial accumulation. Screening of the mitochondrial genome detected novel mutations in the MTND1 gene, encodi...
Source: Clinical Science - January 27, 2015 Category: Biomedical Science Authors: G S Gorman, E L Blakely, H Hornig-Do, H A L Tuppen, L C Greaves, L He, A Baker, G Falkous, J Newman, M I Trenell, B Lecky, R K Petty, D M Turnbull, R McFarland, R W Taylor Source Type: research

Angiotensin II, oxidative stress, and stem cell therapy: a matter of delicacy
Optimisation of stem cell therapy after cardiovascular and renal injury depends on many factors, amongst which stem cell donor health. The renin-angiotensin system (RAS), plays an important role in cardiovascular and renal homeostasis and pathophysiology. It is becoming increasingly clear that the RAS affects the therapeutic performance of stem cells. In the present issue of Clinical Science Kankuri et al. dig deeper into the consequences of excessive angiotensin II signaling and reactive oxygen species (ROS) formation in the stem cell donor, applying a model of regenerative medicine after renal injury. (Source: Clinical Science)
Source: Clinical Science - January 27, 2015 Category: Biomedical Science Authors: A J.M. Roks Source Type: research