bluuebunny/crossref_metadata_2025_split huggingface dataset:
miRNAS in normal and diseased skeletal muscle
Authors: Eisenberg Iris , Alexander Matthew S. , Kunkel Louis M. 
Published: October 2008

Introduction
Mechanisms of miRNA‐mediated repression
miRNA regulatory network in muscle
miRNA signatures as biomarkers of myopathies
miRNA therapeutic promise
Perspective

AbstractThe last 20 years have witnessed major advances in the understanding of muscle diseases and significant inroads are being made to treat muscular dystrophy. However, no curative therapy is currently available for any of the muscular dystrophies, despite the immense progress made using several approaches and only palliative and symptomatic treatment is available for patients. The discovery of miRNAs as new and important regulators of gene expression is expected to broaden our biological understanding of the regulatory mechanism in muscle by adding another dimension of regulation to the diversity and complexity of gene‐regulatory networks. As important regulators of muscle development, unravelling the regulatory circuits involved may be challenging, given that a single miRNA can regulate the expression of many mRNA targets. Although the identification of the regulatory targets of miRNAs in muscle is a challenge, it will be critical for placing them in genetic pathways and biological contexts. Therefore, combining informatics, biochemical and genetic approaches will not only expected to reveal the elucidation of the miRNA regulatory network in skeletal muscle and to bring a better knowledge on muscle tissue regulation but will also raise new opportunities for therapeutic intervention in muscular dystrophies by identifying candidate miRNAs as potential targets for clinical application.
Activation of epidermal growth factor receptor results in Snail protein but not mRNA overexpression in endometrial cancer
Authors: Hipp Susanne , Walch Axel , Schuster Tibor , Losko Sascha , Laux Holger , Bolton T. , Höfler Heinz , Becker Karl‐Friedrich 
Published: October 2008

AbstractReduced E‐cadherin expression is associated with tumour progression of many carcinomas, including endometrial cancers. The transcription factor Snail is known as one of the most prominent transcriptional E‐cadherin repressors; its regulation in cancer tissues, however, still remains unclear. Here, we report that activation of epidermal growth factor receptor (EGFR) resulted in overexpression of Snail and also identified critical downstream signalling molecules. Stimulation of two endometrial carcinoma cell lines with epidermal growth factor (EGF) lead to an increase of Snail protein expression. In primary human endometrioid endometrial carcinomas Snail protein expression correlated with the activated, phosphorylated form of EGFR (Tyr1086) as revealed by profiling 24 different signalling proteins using protein lysate microarrays. In addition, we observed an inverse correlation between Snail and E‐cadherin protein levels in these tumours. Most likely, p38 MAPK, PAK1, AKT, ERK1/2 and GSK‐3β are involved in the up‐regulation of Snail downstream of EGFR. Snail mRNA expression did not show a correlation with activated EGFR in these tumours. Taken together, profiling of signalling proteins in primary human tissues provided strong evidence that EGFR signalling is involved in Snail protein overexpression.
T17b murine embryonal endothelial progenitor cells can be induced towards both proliferation and differentiation in a fibrin matrix
Authors: Bleiziffer Oliver , Horch Raymund E. , Hammon Matthias , Arkudas Andreas , Naschberger Elisabeth , Rath Subha , Pryymachuk Galyna , Beier Justus P. , Hatzopoulos Antonis K. , Stürzl Michael , Kneser Ulrich 
Published: October 2008

AbstractEndothelial progenitor cells (EPC) may enhance blood vessel formation in a variety of clinical settings such as ischaemia and tumour angiogenesis as well as in tissue‐engineered matrices. In the present study, we cultured a murine endothelial progenitor cell line, T17b, in vitro in cell culture as well as in an FDA‐approved fibrin matrix and investigated cell proliferation, differentiation and secretion patterns of the angiogenic growth factor VEGF under hypoxia and differentiation. We show that T17b EPC remain viable for at least 8 days in the fibrin matrix where they proliferate and form clusters including lumen‐like structures. Proliferation in fibrin clots overlayed with basal medium (BM) was confirmed morphologically and immunohistochemically by positive Ki67 staining, indicating mitotic activity. Significant cell proliferation and Ki‐67 expression were absent when cells were incubated with dibutyryl‐cAMP and retinoic acid (RA). Incubation with dibutyryl‐cAMP and RA stimulated the expression of the EPC differentiation markers von Willebrand Factor (vWF) and VEGF receptor 2 (VEGFR‐2), indicating successful differentiation in the fibrin clot. EPC differentiation induced by dibutyryl‐cAMP and RA was confirmed in 2‐D chamber slide cultures by positive vWF immunostaining, which was absent in BM controls. EPC chamber slides also displayed positive vWF staining when exposed to hypoxia under BM conditions, indicating EPC activation and differentiation could also be induced by hypoxia. Taken together, T17b EPC secrete increased levels of VEGF when submitted to either hypoxia or differentiation and can be differentiated into mature endothelial cells not only in cell and matrigel cultures but also in a fibrin matrix that is FDA approved for clinical application.
Reduced ligand affinity leads to an impaired function of the adenosine A2A receptor of human granulocytes in sepsis
Authors: Kreth Simone , Kaufmann Ines , Ledderose Carola , Luchting Benjamin , Thiel Manfred 
Published: October 2008

AbstractThe enhanced release of reactive oxygen species by excessively activated polymorphonuclear leucocytes (PMN) is a key step in the pathogenesis of sepsis. Potent action of adenosine in inhibiting cytotoxic PMN functions has been documented. Recent data, however provide evidence that in sepsis a diminished capability of adenosine to inhibit the generation of oxygen radicals by PMN occurs. Here, we investigated the underlying mechanisms in an in vitro sepsis model and in PMN of sepsis patients. We report that lipopolysaccharide (LPS)‐incubation of human PMN elicited the same increase in the half‐maximal inhibitory concentration (IC50) of adenosine as observed in patients with septic shock. Coupling to adenylyl cyclase was impaired as well, as indicated by a decreased potency of adenosine to stimulate cyclic adenosine monophosphate (cAMP) accumulation. Ligand‐binding studies conducted with native, LPS‐stimulated PMN, and with PMN of sepsis patients revealed that, despite an increased adenosine A2A receptor (A2AR) expression, the receptor function declines due to a diminished ligand‐binding affinity most likely caused by allosteric modulators within the inflammatory environment. A2AR function obviously is highly dependent upon the cellular environment and thus, further functional characterization of A2AR responses in sepsis may be a promising approach to develop new adenosine or A2AR agonists based therapeutic strategies.
A HCMV pp65 polypeptide promotes the expansion of CD4+ and CD8+ T cells across a wide range of HLA specificities
Authors: Provenzano Maurizio , Sais Giovanni , Bracci Laura , Egli Adrian , Anselmi Maurizio , Viehl Carsten T , Schaub Stefan , Hirsch Hans H , Stroncek David F , Marincola Francesco M. , Spagnoli Giulio C 
Published: October 2008

AbstractHuman cytomegalovirus (HCMV) can cause life‐threatening disease in infected hosts. Immunization with human leukocyte antigen (HLA)‐restricted immunodominant synthetic peptides and adoptive transfer of epitope‐specific T cells have been envisaged to generate or boost HCMV‐specific cellular immunity, thereby preventing HCMV infection or reactivation. However, induction or expansion of T cells effective against HCMV are limited by the need of utilizing peptides with defined HLA restrictions. We took advantage of a combination of seven predictive algorithms to identify immunogenic peptides of potential use in the prevention or treatment of HCMV infection or reactivation. Here we describe a pp65‐derived peptide (pp65340–355, RQYDPVAALFFFDIDL: RQY16‐mer), characterized by peculiar features. First, RQY‐16mer is able to stimulate HCMV pp65 specific responses in both CD4+ and CD8+ T cells, restricted by a wide range of HLA class I and II determinants. Second, RQY‐16mer is able to induce an unusually wide range of effector functions in CD4+ T cells, including proliferation, killing of autologous HCMV‐infected target cells and cytokine production. Third, and most importantly, the RQY‐16mer is able to stimulate CD4+ and CD8+ T‐cell responses in pharmacologically immunosuppressed patients. These data suggest that a single reagent might qualify as synthetic immunogen for potentially large populations exposed to HCMV infection or reactivation.
Drug releasing systems in cardiovascular tissue engineering
Authors: Spadaccio Cristiano , Chello Massimo , Trombetta Marcella , Rainer Alberto , Toyoda Yoshiya , Genovese Jorge A. 
Published: October 2008

Introduction
Drug and molecules released
Conclusion
Acknowledgements

AbstractHeart disease and atherosclerosis are the leading causes of morbidity and mortality worldwide. The lack of suitable autologous grafts has produced a need for artificial grafts; however, current artificial grafts carry significant limitations, including thrombosis, infection, limited durability and the inability to grow. Tissue engineering of blood vessels, cardiovascular structures and whole organs is a promising approach for creating replacement tissues to repair congenital defects and/or diseased tissues. In an attempt to surmount the shortcomings of artificial grafts, tissue‐engineered cardiovascular graft (TECVG), constructs obtained using cultured autologous vascular cells seeded onto a synthetic biodegradable polymer scaffold, have been developed. Autologous TECVGs have the potential advantages of growth, durability, resistance to infection, and freedom from problems of rejection, thrombogenicity and donor scarcity. Moreover polymers engrafted with growth factors, cytokines, drugs have been developed allowing drug‐releasing systems capable of focused and localized delivery of molecules depending on the environmental requirements and the milieu in which the scaffold is placed. A broad range of applications for compound‐releasing, tissue‐engineered grafts have been suggested ranging from drug delivery to gene therapy. This review will describe advances in the development of drug‐delivery systems for cardiovascular applications focusing on the manufacturing techniques and on the compounds delivered by these systems to date.
Advances in microRNAs: implications for immunity and inflammatory diseases
Authors: Sonkoly E. , Pivarcsi A. 
Published: October 2008

IntroductionIdentification of microRNA targetsMulti‐level control of microRNA expressionHow can microRNAs contribute to diseases?MiRNAs in immunological and inflammatory disordersMiRNAs in antiviral immunity and viral immune escapePerspectivesAbstractSince their discovery in 1993 and the introduction of the termmicroRNAin 2001, it has become evident that microRNAs (miRNAs) involved in many biological processes, including development, differentiation, proliferation and apoptosis. The function of miRNA the control of protein production in cells by sequence‐specific targeting of mRNAs for translational repression or mRNA degradati Interestingly, immune genes are apparently preferentially targeted by miRNAs compared to the average of the human genome, indicat the significance of miRNA‐mediated regulation for normal immune responses. Here, we review what is known about the role of miRN in the pathogenesis of immune‐related diseases such as chronic inflammatory skin diseases, autoimmunity and viral infections.
Epigenetic programming of μ‐opioid receptor gene in mouse brain is regulated by MeCP2 and brg1 chromatin remodelling factor
Authors: Hwang Cheol Kyu , Song Kyu Young , Kim Chun Sung , Choi Hack Sun , Guo Xiao‐Hong , Law Ping‐Yee , Wei Li‐Na , Loh Horace H. 
Published: October 2008

AbstractThe pharmacological action of morphine as a pain medication is mediated primarily through the μ‐opioid receptor (MOR). With few exceptions, MOR is expressed in brain regions where opioid actions take place. The basis for this unique spatial expression of MOR remains undetermined. Recently, we reported that DNA methylation of the MOR promoter plays an important role in regulating MOR in P19 cells. In this study, we show that the differential expression of MOR in microdissected mouse brain regions coincides with DNA methylation and histone modifications. MOR expression could be induced by a demethylating agent or a histone deacetylase inhibitor in MOR‐negative cells, suggesting that the MOR gene can be silenced under epigenetic control. Increases in the in vivo interaction of methyl‐CpG‐binding protein 2 (MeCP2) were observed in the cerebellum, in which the MOR promoter was hypermethylated and MOR expression was the lowest among all brain regions tested. MeCP2 is associated closely with Rett syndrome, a neurodevelopmental disorder. We also established novel evidence for a functional role for MeCP2’s association with the chromatin‐remodelling factor Brg1 and DNA methyltransferase Dnmt1, suggesting a possible role for MeCP2 in chromatin remodelling during MOR gene regulation. We conclude that MOR gene expression is epigenetically programmed in various brain regions and that MeCP2 assists the epigenetic program during DNA methylation and chromatin remodelling of the MOR promoter.
The potential role of MLC phosphatase and MAPK signalling in the pathogenesis of vascular dysfunction in heart failure
Authors: Ogut Ozgur , Brozovich Frank V. 
Published: October 2008

Clinical syndrome of heart failure
Regulation of smooth muscle contractility
Ca2+ sensitization
Ca2+ desensitization
MYPT1 isoforms and the sensitivity to cGMP
cGMP and MYPT1 phosphorylation
Vascular function and cGMP signalling
Captopril therapy and MYPT1 Expression in HF
Captopril therapy and gene expression
Conclusions
AbstractThe clinical syndrome of heart failure is associated with both a resting vasoconstriction and reduced sensitivity to nitric oxide mediated vasodilatation, and this review will focus on the role of myosin light chain (MLC) phosphatase in the pathogenesis of the vascular abnormalities of heart failure. Nitric oxide mediates vasodilatation by an activation of guanylate cyclase and an increase in the production of cGMP, which leads to the activation of the type I cGMP‐dependent protein kinase (PKGI). PKGI then activates a number of targets that produce smooth muscle relaxation including MLC phosphatase. MLC phosphatase is a holoenzyme consisting of three subunits; a 20 kD subunit of unknown function, an ∼38‐kD catalytic subunit and a myosin targeting subunit (MYPT1). Alternative splicing of a 31 bp 3' exon generates MYPT1 isoforms, which differ by a COOH‐terminus leucine zipper (LZ). Further, PKGI‐mediated activation of MLC phosphatase requires the expression of a LZ+ MYPT1. Congestive heart failure is associated with a decrease in LZ+ MYPT1 expression, which results in a decrease in the sensitivity to cGMP‐mediated smooth muscle relaxation. Beyond their ability to reduce afterload, angiotensin converting enzyme (ACE) inhibitors have a number of beneficial effects that include maintaining the expression of the LZ+ MYPT1 isoform, thereby conserving normal sensitivity to cGMP‐mediated vasodilatation, as well as differentially regulating genes associated with mitogen activated protein kinase (MAPK) signalling. ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways, possibly preventing the alteration of the vascular phenotype to preserve normal vascular function.
Intraplaque injection of Ad5‐CMV.p53 aggravates local inflammation and leads to plaque instability in rabbits
Authors: Zhang Lei , Liu Yan , Lu Xiao Ting , Xu Xin Sheng , Zhao Yu Xia , Ji Xiao Ping , Zhang Peng Fei , Liu Chun Xi , Tang Meng Xiong , Chen Wen Qiang , Zhang Yun 
Published: October 2008

AbstractThis study aims to develop a new animal model of vulnerable plaques and investigate the potential mechanisms of exogenous p53‐induced plaque instability. Forty rabbits underwent aortic balloon injury, were fed a 1% cholesterol diet for 10 weeks and then normal chow for 6 weeks. Rabbits were divided into Ad5‐CMV.p53‐treated group (n= 16), Ad5‐CMV.lac Z‐treated group (n= 16) and blank control group (n= 8). Under the guidance of intravascular ultrasound, a 50‐μl suspension of adenovirus containing p53 or lac Z was injected into the largest plaque of the first two groups, respectively, and these rabbits received pharmacological triggering 2 weeks later. In 76.9% of rabbits with p53 transfection, plaque rupture was found, which was significantly (P < 0.05) higher than that in the Ad5‐CMV.lac Z‐treated plaques (23.1%), or blank controls plaques (0%). Increased apoptotic cells, and subsequently, decreased vascular smooth muscle cells and collagen content, enhanced intima macrophage accumulation, increased C‐reactive protein (CRP) and matrix metalloproteinases staining and high serum levels of high sensitive CRP (hs‐CRP) and monocyte chemoattractant protein‐1 (MCP‐1) were observed in Ad5‐CMV.p53‐treated rabbits. However, a binary logistic regression model revealed that hs‐CRP concentration rather than apoptosis rate played an independent role in plaque rupture with an odds ratio as 1.314 (95% CI: 1.041–1.657, P= 0.021), and there were high positive correlations between inflammatory biomarkers (hs‐CRP or MCP‐1) and apoptosis (R2= 0.761, and R2= 0.557, respectively, both P < 0.01). Intraplaque injection of p53 gene provides a safe and effective method for inducing plaque vulnerability in rabbits. The destabilizing effect of p53 overexpression is mediated mainly through apoptosis‐enhanced inflammation rather than cell apoptosis itself.
Combination of taxol and Bcl‐2 siRNA induces apoptosis in human glioblastoma cells and inhibits invasion, angiogenesis and tumour growth
Authors: George Joseph , Banik Naren L. , Ray Swapan K. 
Published: October 2008

AbstractTaxol is a powerful chemotherapeutic agent that binds to microtubules to prevent tumour cell division. However, a traditional high dose of taxol may also induce apoptosis in normal cells. The anti‐apoptotic molecule Bcl‐2 is up‐regulated in tumour cells to prevent apoptosis. We designed this study to determine whether use of a low dose of taxol and anti‐apoptotic Bcl‐2 gene silencing would effectively induce apoptosis in human glioblastoma U251MG cells and also inhibit invasion, angiogenesis and intracranial as well as subcutaneous tumour growth. We treated the cells with either 100 nM taxol or transfected with a plasmid vector expressing Bcl‐2 siRNA or both agents together for 72 h. Knockdown of Bcl‐2 potentiated efficacy of taxol for cell death. Fluorescence‐activated cell sorting analysis, double immunofluorescent staining and TUNEL assay demonstrated apoptosis in about 70% of the cells after treatment with the combination of taxol and Bcl‐2 siRNA. In vitro Matrigel invasion assay demonstrated dramatic decrease in glioblastoma cell invasion and in vivo angiogenesis assay showed complete inhibition of neovascularization in athymic nude mice after treatment with the combination. Further, treatment with the combination of taxol and Bcl‐2 siRNA caused suppression of intracranial tumour growth and subcutaneous solid tumour development. In conclusion, our results indicate that the combination of taxol and Bcl‐2 siRNA effectively induces apoptosis and inhibits glioblastoma cell invasion, angiogenesis and intracranial as well as subcutaneous tumour growth. Therefore, the combination of a low dose of taxol and Bcl‐2 siRNA is a promising therapeutic strategy for controlling the aggressive growth of human glioblastoma.
Let‐7 repression leads to HMGA2 overexpression in uterine leiomyosarcoma
Authors: Shi Guizhi , Perle Mary Ann , Mittal Khush , Chen Hua , Zou Xuanyi , Narita Masashi , Hernando Eva , Lee Peng , Wei Jian‐Jun 
Published: October 2008

AbstractOverexpression of HMGA2 is common in uterine leiomyomas (ULM). The expression of HMGA2 in its malignant counterpart – uterine leiomyosarcomas (ULMS) remains undetermined. Recently it has been shown that repression of HMGA2 by microRNA let‐7s is a critical molecular regulatory mechanism associated with tumour growth in many tumours and cell types, including leiomyomas. To test whether HMGA2 and let‐7s play a role in ULMS, we examined the levels of endogenous HMGA2 and let‐7 expression and found a significant correlation between these two molecules in a case‐matched cohort of human ULMS. We found that overexpression of HMGA2 and let‐7‐mediated HMGA2 repression is a relevant molecular alteration in ULMS. Disrupting the control of HMGA2 and let‐7 pairs promotes ULMS cell growth in vitro.
The missing link between indoleamine 2,3‐dioxygenase mediated antibacterial and immunoregulatory effects
Authors: Müller Anika , Heseler Kathrin , Schmidt Silvia K. , Spekker Katrin , MacKenzie Colin R. , Däubener Walter 
Published: October 2008

AbstractThe interferon (IFN)–γ‐inducible tryptophan degrading enzyme indoleamine 2,3‐dioxygenase (IDO) has not only been recognized as a potent antimicrobial effector molecule for the last 25 years but was recently found also to have potent immunoregulatory properties. In this study, we provide evidence that both tryptophan starvation and production of toxic tryptophan metabolites are involved in the immunoregulation mediated by IDO, whereas tryptophan starvation seems to be the only antibacterial effector mechanism. A long‐studied controversy in the IDO research field is the seemingly contradictory effect of IDO in the defence against infectious diseases. On the one hand, IFN‐γ‐induced IDO activity mediates an antimicrobial effect, while at the same time IDO inhibits T‐cell proliferation and IFN–γ production. Here, we suggest that both effects, dependent on the threshold for tryptophan, cooperate in a reasonable coherence. We found that the minimum concentration of tryptophan required for bacterial growth is 10‐40‐fold higher than the minimum concentration necessary for T‐cell activation. Therefore, we suggest that during the first phase of infection the IDO‐mediated tryptophan depletion has a predominantly antimicrobial effect whereas in the next stage, and with ongoing tryptophan degradation, the minimum threshold concentration of tryptophan for T‐cell activation is undercut, resulting in an inhibition of T‐cell growth and subsequent IDO activation.