Val119 has lower activity and thermal stability but increased affinity for endogenous substrates. Studies

suggest that heterozygosity for Val/Ile favors efficient isoaspartate repair. We have performed multiple molecular dynamics simulations of 119I and 119V PIMT. Both V119 and I119 interact with the same residues throughout all of the simulations. However, the larger Ile altered the orientations of alpha 5 and beta 5, both of which have co-substrate binding residues on their distal ends. I119 increases the flexibility of several residues, loosening up the S-adenosylmethionine (SAM)-binding site. These subtle changes are propagated towards the isoaspartate-docking site via residues common to both active sites. The increased mobility in 119I PIMT reorients alpha 3, resulting in a salt-bridge network at the substrate-binding interface that disrupts several key side-chain interactions in the isoaspartate site. LEE011 In contrast, 119V PIMT remains quite rigid with little change to the co-substrate binding site, which could hinder SAM’s binding Selleck PS341 and release, accounting for the decreased activity. These results shed light on the molecular basis behind the decreased activity and increased specificity for endogenous substrates

of 119V PIMT relative to the 119I variant. 119I PIMT catalyzes the methylation reaction but may have difficulties recognizing and orienting specific substrates due to its distorted substrate-binding site. Heterozygosity for both the Ile and Val alleles may provide the best of both worlds, allowing Fluocinolone acetonide the fast and specific methylation of damaged proteins.”
“The aim of the study was to extend the survival of adult spinal motor neurons in serum free culture. Anterior half of the spinal cord was removed from young

adult mice and dissociated. Cultured cells attempted to extend neurites within hours of incubation at 37 degrees C and died within 24 h. To prevent this early regenerative activity, thus to decrease the metabolic requirements of the neurons, cultures were transferred to 4 degrees C immediately after they were set and kept there for 3 days. Preparations were then taken to 37 degrees C where they lived up to 8 days. Some neurons continued to extend neurites until the day they died. To understand whether the enhancement of survival involves new protein synthesis, transcription and translation were blocked during cold pre-incubation, which shortened the half life of neurons but not changed the maximum survival period. In conclusion this study has shown that, in the serum-free cultures, the survival of adult spinal motor neurons can be significantly enhanced by cold pre-incubation whose effect seems to depend largely on a reduction in the metabolic activity and less on new protein synthesis. (c) 2012 Elsevier Ireland Ltd. All rights reserved.”
“The ORF3 protein of hepatitis E virus (HEV) is a multifunctional protein important for virus replication.

Partial but significant overlap was revealed with

previous proteomics and transcriptomics studies in colorectal carcinoma. Among upregulated proteins we identified 3-HMG-CoA synthase, protein phosphatase 1, prostaglandin E synthase 2, villin 1, annexin A1, triosephosphate isomerase, phosphoserine aminotransferase 1, fumarylacetoacetate hydrolase and CB-5083 manufacturer pyrroline-5-carboxylate reductase 1 (PYCR1), while glucose-regulated protein 78, cathepsin D, lamin A/C and quinolate phosphoribosyltransferase were downregulated.”
“Integrin alpha(4)beta(1) (also called very late antigen-4 or VLA-4) plays an-important role in tumor growth, angiogenesis and metastasis, and there has been increasing interest in targeting this receptor for cancer imaging and therapy. In this study, we conjugated a peptidomimetic ligand known to have good DihydrotestosteroneDHT ic50 binding affinity for alpha(4)beta(1) integrin to a cross-bridged macrocyclic chelator with a methane phosphonic acid pendant arm, CB-TE1A1P. CB-TE1A1P-LLP2A was labeled with Cu-64 under mild conditions in high specific activity, in contrast to conjugates based on the “”gold standard”" di-acid cross-bridged chelator, CB-TE2A, which require high temperatures for efficient radiolabeling. Saturation

binding assays demonstrated that Cu-64-CB-TE1A1P-LLP2A had comparable binding affinity (1.2 nM vs 1.6 nM) but more binding sites (B-max = 471 fmol/mg) in B16F10 melanoma tumor cells than Cu-64-CB-TE1A1P-LLP2A (B-max = 304 fmol/mg, p<0.03). In biodistribution studies, Cu-64-CB-TE1A1P-LLP2A had less renal retention but higher uptake in tumor (11.4+/-2.3 %ID/g versus 3.1+/-0.6 %ID/g, p<0.001) and other receptor-rich tissues compared to Cu-64-CB-TE2A-LLP2A. At 2 h post-injection, 64Cu-CB-TE1A1P-LLP2A also had significantly higher tumor:blood and tumor:muscle ratios than Cu-64-CB-TE2A-LLP2A (CB-TE1A1P = 19.5+/-3.0 and 13.0+/-1.4, respectively, CB-TE2A = 4.2+/-1.4 and 5.5+/-0.9, respectively, p<0.001). These data demonstrate that Cu-64-CB-TE1A1P-LLP2A

and is an excellent PET radiopharmaceutical for the imaging of alpha(4)beta(1) positive tumors and also has potential for imaging other alpha(4)beta(1) positive cells such as those of the pre-metastatic niche. (C) 2013 Elsevier Inc. All rights reserved.”
“Purpose: Collagenase Clostridium histolyticum is an investigational nonsurgical treatment for Peyronie disease. In this phase 2b, double-blind, randomized, placebo controlled study we determined the safety and efficacy of collagenase C. histolyticum and assessed a patient reported outcome questionnaire.

Materials and Methods: A total of 147 subjects were randomized into 4 groups to receive collagenase C. histolyticum or placebo (3: 1) with or without penile plaque modeling (1: 1). Per treatment cycle 2 injections of collagenase C. histolyticum (0.58 mg) were given 24 to 72 hours apart.

Activation of the dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32) intracellular cascade mediates responses to cocaine.

To examine the possibility that acute cocaine administration alters the DARPP-32 cascade in a sexually dimorphic pattern.

Male and Z-IETD-FMK clinical trial female rats received either saline or cocaine (30 mg/kg). Protein levels of DARPP-32, phosphorylation of DARPP-32 at the Thr34 site (P-Thr34-DARPP-32), protein phosphatase 1 (PP-1), and protein phosphatase 2B (PP-2B) in nucleus accumbens were measured via

Western blot analysis.

Females had higher protein levels of DARPP-32, P-Thr34-DARPP-32, calcineurin A (CaN-A; catalytic subunit of PP-2B), and calcineurin B (CaN-B; regulatory subunit of PP-2B) than males 5 min after saline treatment. In females, CaN-A protein levels were also higher at 15 min and PP-1 protein levels were higher 30 min after saline administration than males. In male rats, cocaine significantly increased CaN-A protein levels at 30 min and CaN-B protein levels at 15 min. In females, cocaine administration significantly decreased protein levels of DARPP-32, P-Thr34-DARPP-32,

and CaN-A at 45 min but increased PP-1 protein levels at 30 min. Overall, males had higher activation of the DARPP-32 pathway after cocaine administration than did females.

These novel results show that basal and cocaine-induced sex differences in the DARPP-32/PP-1 cascade may be responsible for the sexual dimorphism in acute cocaine-induced behavioral responses.”
“Objective: Tc-99m-Sn-PYP (Technetium-99(m) labeled tin pyrophosphate) has Selleckchem Pitavastatin been widely used as a radiopharmaceutical for bone scanning as well as in nuclear cardiology. It is also found in the body in trace amounts. Lu-177 is presently considered as an excellent radionuclide for developing bone pain palliation agents. PYP is an analogue of MDP and MDP has been labeled with Lu-177. No study on preparing a complex of Lu-177 with PYP has been reported yet. Based on these facts, it was hypothesized that a bone-seeking Celastrol Lu-177-PYP (Lutetium-177 labeled Pyrophosphate) radiopharmaceutical could be developed as

an agent for palliative radiotherapy of bone pain due to skeletal metastases.

Methods: Lu-177 was produced by irradiating lutetium foil (11 mg) natural target at a flux similar to 1.0 x 10(14)n/cm(2)/s for 12 h in the swimming pool type reactor. Lu-177 in the form of (LuCl3)-Lu-177 was labeled with PYP. The radiochemical purity and labeling efficiencies were determined by paper chromatography. Labeling of Lu-177 with PYP was optimized and a labeled sample was subjected to HPLC analysis. To determine the charge on the Lu-177-PYP complex, radio-electrophoresis was conducted for 1 h under a voltage of 300 V and 45 mA current using 0.025 M phosphate buffer (pH 6.9). Bioevaluation studies with rabbit under gamma-camera were also performed to verify the skeletal uptake.

(C) 2012 Elsevier Ltd. All rights reserved.”
“Some authors have reported an association of BDNF Val66Met polymorphism with suicidal behavior and/or clinical aspects of

suicidal attempts. We evaluated, here, the impact of BDNFVal66Met polymorphism on the clinical characteristics of suicide attempts. The study was conducted on a cohort of 120 consecutive patients who were admitted to the Emergency Hospital of Porto Alegre, Brazil, due to a suicide attempt. Variables of univariate analyses were included in a logistic regression model to test whether the risk factors had independent effect. In univariate PCI32765 analyses, sex, BDNF genotype, intent and method of suicide attempt were all risk factors for high lethality in suicide attempts. After logistic regression analysis, male sex (O.R.=3.03; 95% C.I = 1.34-6.84; 0.008) and the presence of BDNF 66Met allele (O.R.= 2.62; 95% C.I = 1.04-6.57; 0.04) were significantly and independently associated with the high lethality in suicide attempts. The present study showed that BDNF 66Met allele is an independent predictor of high lethality BIX 1294 concentration in suicide

attempts of depressed patients. This finding is important because it might allow earlier identification of patients at high risk for suicide, perhaps providing better tools for clinical care of these patients in the future. (C) 2010 Elsevier Inc. All rights reserved.”
“The use of glucagon-like peptide-1 (7-36) amide (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus is commonly associated with nausea and vomiting. Therefore,

the present studies investigated the potential of GLP-1 receptor ligands to modulate emesis and feeding in Suncus murinus. Exendin-4, a selective GLP-1 receptor agonist, was administered subcutaneously Adenylyl cyclase (1-30 nmol/kg) or intracerebroventricularly (0.03-3 nmol) after 12-h of fasting. In other studies, animals were pretreated with the GLP-1 receptor antagonist, exendin (9-39), or saline (5 mu l) 15 min prior to exendin-4 (3 nmol, i.c.v.). Behaviour of animals and food and water intake were then recorded for 1-2 h; c-Fos expression was also assessed in the brains of animals in the i.c.v. studies. The subcutaneous administration of exendin-4 reduced food and water intake (p < 0.001) and induced emesis in 40% of animals (p > 0.05). The intracerebroventricular administration of exendin-4 also prevented feeding, and induced emesis (p < 0.01). In these studies, exendin (9-39) (30 nmol, i.c.v.) antagonised emesis induced by exendin-4 and the increased c-Fos expressions in the brainstem and hypothalamus (p < 0.05), but it was ineffective in reversing the exendin-4-induced inhibition of food and water intake (p > 0.05). These data suggest that exendin-4 exerts its emetic effects in the brainstem and/or hypothalamus via GLP-1 receptors. The action of exendin-4 to suppress feeding may involve non-classical GLP-1 receptors or other mechanisms.

Our results show that progeny exposed to early life ethanol displayed increased consumption of ethanol solutions and increased sensitivity to cocaine rewarding effects assessed in the conditioned place preference test. Offspring exposed to ethanol were more LY2090314 mouse sensitive to the anxiolytic effect of ethanol and the increased sensitivity could, at least in part,

explain the alteration in the consumption of ethanol for its anxiolytic effects. In addition, the sensitivity to hypothermic effects of ethanol and ethanol metabolism were not altered by early life ethanol exposure. The sensitization to cocaine (20 mg/kg) and to amphetamine (1.2 mg/kg) was increased after early life ethanol find more exposure and, could partly explain, an increase in the rewarding properties of psychostimulants. Gene expression analysis revealed that expression of a large number of genes was altered in brain regions involved in the reinforcing effects of drugs of abuse. Dopaminergic receptors and transporter

binding sites were also down-regulated in the striatum of ethanol-exposed offspring. Such long-term neurochemical alterations in transmitter systems and in the behavioral responses to ethanol and other drugs of abuse may confer an increased liability for addiction in exposed offspring. (C) 2008 Elsevier Ltd. All rights reserved.”
“Objective: The effect of seasonal variation on cardiac surgery outcomes is unknown. We investigated the effect of season on risk-adjusted hospital mortality and length of stay.

Methods: Prospectively collected data from cardiac operations at one center between April 1996 and March 2006 were analyzed. Seasonal variation in outcomes was studied by using multiple regression models that included EuroSCORE and year of operation to adjust Histidine ammonia-lyase for risk profile and changes over time.

Analysis was performed for 2 separate surgical groups: patients having coronary artery bypass grafting only and patients having other cardiac procedures with or without coronary artery bypass grafting.

Results: There were 16,290 patients who had a first record of cardiac surgery in the study period between April 1, 1996, and March 31, 2006, with 10,263 patients having coronary artery bypass grafting only and 6027 patients having another procedure with or without coronary artery bypass grafting. There were increased odds of hospital mortality in patients having operations in winter compared with the average across all seasons for both surgical groups, although this was only significant in the coronary artery bypass grafting -only group (odds ratio, 1.29; 95% confidence interval, 1.01 -1.63; P=.04). There were decreased odds of death in the coronary artery bypass grafting -only group in summer (odds ratio, 0.76; 95% confidence interval, 0.60 -0.96; P = .02).

The exciting advances in basic science are paralleled by the recognition from clinical investigations that neuropathic pain is not a monolithic entity, but instead presents

as a composite of pain and other sensory symptoms. Attempts are under way to supplement the traditional classification with a classification that links pain and sensory symptoms with neurobiological mechanisms. This mechanism-or symptom-based classification takes both negative and positive sensory symptoms into account. By using a battery of several standardized quantitative sensory tests, the characteristic profile of sensory symptoms can be elucidated in each patient. Moreover, in questionnaires the verbal descriptors can depict the quality and intensity of the individual pain. The approach of classifying and subgrouping patients with neuropathic pain on the basis of symptoms H 89 mouse or signs opens up new possibilities for stratifying patients in clinical trials. First,

in clinical proof-of-concept trials the study population can be enriched prospectively on the basis of entry criteria defined a priori. This enrichment with patients who potentially require a specific treatment should increase the likelihood for positive trial outcomes. Second, in clinical practice it becomes possible to establish an individualized therapy-that is, to identify the particular patients who require a specific treatment option.”
“Purpose: Studies suggest that patients who undergo thorough lymphadenectomy for bladder cancer benefit from improved survival. We evaluated the incidence of and trends in lymphadenectomy in EPZ-6438 conjunction

with radical cystectomy for bladder cancer.

Materials and Methods: Using the Surveillance, Epidemiology DNA ligase and End Results registry we identified 8,072 eligible patients with bladder cancer who underwent radical cystectomy with or without lymphadenectomy from 1988 to 2004. After stratification by age group, race, stage, grade and year of diagnosis we performed logistic and linear regression to correlate variables to the mean number of lymph nodes sampled and the likelihood of undergoing lymphadenectomy (classified as I or more, 5 or more and 10 or more nodes removed).

Results: In the final cohort 1,660 patients (21%) did not have any lymph nodes sampled at radical cystectomy. This number decreased from 37% in 1988 to 16% in 2004. During this period the mean number of lymph nodes removed increased by 2.6 nodes over all definitions of lymphadenectomy and the percentage of patients undergoing any form of lymph node dissection increased by an average of 19%. Year of diagnosis was most strongly predictive of the likelihood of undergoing lymphadenectomy and most correlative with the mean number of nodes sampled.

Conclusions: Over time there has been improvement in terms of the performance of lymphadenectomy and node counts obtained during radical cystectomy.

The present fMRI study explored working memory for emotional stimuli in 16 patients with amnestic MCI (aMCI) and 16 healthy aged participants. Subjects performed an n-back task (2-back) with learn more neutral, positive, and negative emotional pictures. The analysis focused on target processing. Results showed that groups did not differ in working memory performance. In healthy aged participants emotional targets had no significant impact on working memory. In patients with aMCI a negativity bias was observed, indicating that negative targets were better remembered compared to neutral and positive targets. Regarding fMRI

results, both groups showed an increase in functional activity in prefrontal and lateral parietal brain regions associated with target processing. As a key result, we observed significant group by emotion interaction effects in the precuneus. Healthy aged participants showed a signal decrease in the left precuneus for positive compared to neutral targets. The precuneus deactivation in healthy aged participants may indicate a disengagement of self-referential processes towards task-related processes. Patients with aMCI revealed a signal increase in the right precuneus for negative compared to neutral

targets. This increase in precuneus activity, combined with a behavioural facilitation effect, may indicate a mechanism to compensate disease related processes in aMCI. (C) 2007 Elsevier Ltd. All rights reserved.”
“Here we describe a strategy to fluorescently label the envelope of rabies virus (RV), of the Rhabdoviridae family, in order to track the transport of Protein Tyrosine Kinase inhibitor single enveloped Selleckchem Epacadostat viruses in living cells. Red fluorescent proteins (tm-REP) were engineered to comprise the N-terminal signal sequence and C-terminal

transmembrane spanning and cytoplasmic domain sequences of the RV glycoprotein (G). Two variants of tm-RFP were transported to and anchored in the cell surface membrane, independent of glycosylation. As shown by confocal microscopy, tm-RFP colocalized at the cell surface with the RV matrix and G protein and was incorporated into G gene-deficient virus particles. Recombinant RV expressing the membrane-anchored tm-RFP in addition to G yielded infectious viruses with mosaic envelopes containing both tm-RFP and G. Viable double-labeled virus particles comprising a red fluorescent envelope and a green fluorescent ribonucleoprotein were generated by expressing in addition an enhanced green fluorescent protein-phosphoprotein fusion construct (S. Finke, K. Brzozka, and K. K. Conzelmann, J. Virol. 78:12333-12343, 2004). Individual enveloped virus particles were observed under live cell conditions as extracellular particles and inside endosomal vesicles. Importantly, double-labeled RVs were transported in the retrograde direction over long distances in neurites of in vitro-differentiated NS20Y neuroblastoma cells.

Additional analyses were AG-120 solubility dmso done with finer categorisation of heart rate, and with heart rate as a continuous variable.

Findings After adjustment for baseline characteristics,

patients with heart rates of 70 bpm or greater had increased risk for cardiovascular death (34%, p=0.0041), admission to hospital for heart failure (53%, p<0.0001), admission to hospital for myocardial infarction (46%, p=0.0066), and coronary revascularisation. (38%, p=0.037). For every increase of 5 bpm, there were increases in cardiovascular death (8%, p=0.0005), admission to hospital for heart failure (16%, p<0.0001), admission to hospital for myocardial infarction (7%, p=0.052), and coronary revascularisation. (8%, p=0.034). The analysis of fine-groupings of heart rate suggests that the increase in mortality and heart failure outcomes rises continuously above 70 bpm, whereas the relation is less pronounced for coronary outcomes. For heart failure outcomes, the predictive value of resting heart rate was stronger for earlier events than for later events.

Interpretation In patients SC75741 cell line with coronary artery disease and left-ventricular systolic dysfunction, elevated heart rate

(70 bpm or greater) identifies those at increased risk of cardiovascular outcomes, with a differential effect on outcomes associated with heart failure and outcomes associated with coronary events.

Funding Servier, France.”
“Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily characterized by excessive deposition of amyloid-beta (A beta) peptides in the brain. One of the earliest neuropathological changes

in AD is the presence of a high number of reactive astrocytes at sites of A beta deposition. Molecular motor Disturbance of glutamatergic neurotransmission and consequent excitotoxicity is also believed as implicated in the progression of this dementia. Therefore, the study of astrocyte responses to A beta, the main cellular type involved in the maintenance of synaptic glutamate concentrations, is crucial for understanding the pathogenesis of AD. This study aims to investigate the effect of A beta on the astrocytic glutamate transporters, glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST), and their relative participation to glutamate clearance. In addition we have also investigated the involvement of mitogen-activated protein (MAP) kinases in the modulation of GLT-11 and GLAST levels and activity and the putative contribution of oxidative stress induced by A beta to the astrocytic glutamate transport function. Therefore, we used primary cultures of rat brain astrocytes exposed to AV synthetic peptides.

The combination also demonstrated an essential reversal of biochemical alterations. Nitrotyrosine and Poly ADP Ribose (PAR) immunopositivity was significantly decreased in sciatic nerve micro-sections of treatment group. The results of this study advocate that simultaneous inhibition of oxidative stress-PARP activation cascade

may prove useful for the pharmacotherapy of DN. (C) 2009 Elsevier Ltd. All rights reserved.”
“Glutamate receptor-mediated changes in intracellular Ca(2+) may have important implications for activity-dependent regulation of early embryonic development. Etomoxir supplier NMDA receptors were originally considered to be the sole source of glutamate-mediated Ca(2+) influx. However, AMPA receptors lacking AICAR order the GluR2 subunit also allow a significant influx of Ca(2+) ions. Although Ca(2+)-permeable AMPA receptors are a familiar feature in developing neurons, the developmental function of these receptors during the formation of the nervous system remains to be established. Previously, we have demonstrated that chicken lumbar motoneurons express Ca(2+)-permeable AMPA receptors at embryonic day (E) 6. The Ca(2+) permeability of AMPA receptors decreases three-fold by E11. In this study we explored the role of transiently expressed Ca(2+)-permeable AMPA receptors in regulating the dendritic morphology of developing motoneurons in ovo. The AMPA receptor blocker CNQX (1 mg/day), when applied between E5 and

E8, causes a significant increase in dendritic outgrowth and branching as compared with vehicle-treated embryos. Inhibition of NMDA receptor activity with MK-801 (100 mu g/day) during this period has no effect on dendritic morphology. Treatment of chicken embryos with CNQX between E8 and E11 (when most receptors become Ca(2+) impermeable) has no significant effect on dendritic morphology. However, MK-801 application between E8 and E11 causes a significant reduction in

dendritic length and branching. These findings indicate that AMPA receptor activation between E5 and E8 limits dendritic outgrowth in developing motoneurons, whereas NMDA receptor activation is involved in dendritic remodeling after the establishment of synaptic contacts with sensory afferents. (C) 2009 Elsevier Ltd. All rights reserved.”
“Adult already outbred Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively). Importantly, LCRs and HCRs are distinguished by their differential responsiveness to acute cocaine-induced (but not baseline) locomotor activity, inhibition of the dopamine transporter (DAT) and resulting extracellular DA (HCR > LCR), as well as by repeated cocaine-induced locomotor sensitization and measures of cocaine’s rewarding and reinforcing effects (LCR > HCR). Curiously, 30 min after acute cocaine HCRs exhibit greater DAT-mediated [(3)H]DA uptake into striatal synaptosomes than LCRs.

RESULTS: The majority (88.74%) of California’s CES patients received surgery within the recommended 48-hour window after diagnosis. The incidence of CES in surgically treated degenerative lumbar disk patients was 1.51% with an average of 397 cases per year in California. CES patients had worse outcomes and used more healthcare resources than other surgically treated degenerative lumbar disk patients; this disparity was more pronounced for patients with advanced CES. CES patients treated after 48 hours had 3 times the odds of a nonroutine discharge as patients treated within 48 hours (odds ratio = 3.082; P < .001).

CONCLUSION:

In California, patients are being treated within the recommended 48-hour time frame.”
“Objective: The

present study was aimed at developing a new cell-permeant peptide inhibitor (MK2i) of the kinase that phosphorylates selleck chemicals llc Dasatinib concentration and activates heat-shock protein (HSP)27 (MAPKAP kinase II), and evaluating the ability of this peptide to inhibit HSP27 phosphorylation and intimal thickening.

Methods: The ability of MK2i to reduce HSP27 phosphorylation and cell migration was evaluated in A7R5 cells stimulated with arsenite or lysophosphatidic acid. Stable isotopic labeling using amino acids in cell culture, in combination with liquid chromatography mass spectrometry, was used to characterize the effect of MK2i on global protein expression in fibroblasts. The effect of MK2i on intimal thickening and connective tissue growth factor expression was evaluated in human saphenous vein (HSV) rings maintained with 30% fetal bovine serum for 14 days by light microscopy and immunoblotting.

Results: Pretreatment of cells

with MK2i (10 mu M) prior to arsenite Terminal deoxynucleotidyl transferase or lysophosphatidic acid stimulation decreased phosphorylation of HSP27 (36% +/- 9% and 33% +/- 10%, respectively) compared with control (not pretreated) cells. MK2i also inhibited A7R5 migration, and downregulated the transforming growth factor-induced expression of collagen and fibronectin in keloid cells, two major matrix proteins involved in the development of intimal hyperplasia. Treatment of HSV segments with MK2i enhanced relaxation, reduced HSP27 phosphorylation (40% +/- 17%), connective tissue growth factor expression (17% +/- 5%), and intimal thickness (48.2% +/- 10.5%) compared with untreated segments. On the other hand, treatment with a recombinant fusion protein containing a cell-permeant peptide attached to the HSP27 sequence increased intimal thickness of HSV segments by 48% +/- 14%.

Conclusion: Our results suggest that HSP27 may play a role in the development of processes leading to intimal hyperplasia in HSV, and reduction of HSP27 phosphorylation by MK2i may be a potential strategy to inhibit the development of intimal hyperplasia in HSV to prevent the autologous vascular graft failure. ( J Vase Surg 2010;52:1596-1607.