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1.
Transforming growth factor β (TGF-β) is a growth factor presenting important functions during tissue remodeling and hypertrophic scar (HS) formation. However, the underlying molecular mechanisms are largely unknown. In this study, we identified thrombospondin-4 (TSP-4) as a TGF-β1 target that essentially mediates TGF-β1-induced scar formation both in vitro and in vivo. The expression of TSP-4 was compared on both mRNA and protein levels between hypertrophic scar fibroblasts (HSFs) and normal skin fibroblast (NFs) in response to TGF-β1 treatment. Two signaling molecules, Smad3 and p38, were assessed for their importance in regulating TGF-β1-mediated TSP-4 expression. The significance of TSP-4 in controlling TGF-β1-induced proliferation, invasion, migration, and fibrosis in HSFs was analyzed by knocking down endogenous TSP-4 using small hairpin RNA (shRNA) (TSP-4 shRNA). Finally, a skin HS model was established in rats and the scar formation was compared between rats treated with vehicle (saline), TGF-β1, and TGF-β1 + TSP-4 shRNA. The TSP-4 level was significantly higher in HSFs than in NFs and TGF-β1 more potently boosted TSP-4 expression in the former than in the latter. Both Smad3 and p38 essentially mediated TGF-β1-induced TSP-4 expression. TSP-4 shRNA significantly suppressed TGF-β1-stimulated proliferation, invasion, migration, or fibrosis of HSFs in vitro and drastically improved wound healing in vivo. TGF-β1, by activating both Smad3 and p38, induces TSP-4, which in turn not only presents a positive feedback regulation on the activation of Smad3 and p38, but also essentially mediates TGF-β1-induced HS formation. Targeting TSP-4 thus may benefit HS treatment. 相似文献
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Stretch-induced paracrine hypertrophic stimuli increase TGF-β1 expression in cardiomyocytes 总被引:2,自引:0,他引:2
van Wamel AJ Ruwhof C van der Valk-Kokshoorn LJ Schrier PI van der Laarse A 《Molecular and cellular biochemistry》2002,236(1-2):147-153
Cardiac hypertrophy refers to the abnormal growth of cardiomyocytes, and is often caused by valvular heart disease and hypertension. It involves the activation of growth, including increased protein synthesis and changes in gene expression. Transforming growth factor-1 (TGF-1) may play a central role in protecting the heart during the hypertrophic response by helping to restore normal functions of the affected myocardium. We tested the hypothesis that cardiomyocytes respond to stretch-induced paracrine hypertrophic stimuli with increased expression of TGF-1. To that purpose, we investigated whether angiotensin II (AII), endothelin-1 (ET-1) and TGF-, secreted by stretched cardiac and vascular cells, are involved in the paracrine mechanisms of stretch-induced changes of TGF-1 mRNA expression in stationary (i.e. non-stretched) cardiomyocytes.Our results indicated that TGF-1 mRNA expression in stationary cardiomyocytes was increased by AII release from cardiomyocytes that had been stretched for 30–60 min. Furthermore, it is likely that ET-1 and TGF- were released by stretched cardiac fibroblasts and endothelial cells to induce TGF-1 mRNA expression in stationary cardiomyocytes. Stretched vascular smooth muscle cells did not influence TGF-1 mRNA expression in stationary cardiomyocytes. These results indicate that AII, ET-1 and TGF-, released by cardiac cell types, act as paracrine mediators of TGF-1 mRNA expression in cardiomyocytes. Therefore, we conclude that in stretched myocardium the cardiomyocytes, cardiac fibroblasts and endothelial cells take part in intercellular interactions contributing to cardiomyocyte hypertrophy. 相似文献
3.
Bos JM Subramaniam M Hawse JR Christiaans I Rajamannan NM Maleszewski JJ Edwards WD Wilde AA Spelsberg TC Ackerman MJ 《Journal of cellular biochemistry》2012,113(6):1896-1903
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10‐encoded TGFβ Inducible Early Gene‐1 knock‐out mice (TIEG?/?) develop HCM with 13‐fold up‐regulation of PTTG1‐encoded pituitary tumor‐transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's four translated exons using DHPLC and direct DNA‐sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase‐assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in six patients (two males/four females, mean age at diagnosis 56.2 ± 23 years, MLVWT 20.8 ± 4 mm). Compared to WT TIEG1, five TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1?/?‐mice. By IHC, PTTG1‐protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1‐mutation positive HCM compared to normal hearts. This is the first article to associate mutations in TIEG1 to human disease with the discovery of six novel, HCM‐associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1‐mediated HCM. Up‐regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1‐mediated HCM. J. Cell. Biochem. 113: 1896–1903, 2012. © 2012 Wiley Periodicals, Inc. 相似文献
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David R. Bauman Alan Whitehead Lisa C. Contino Jisong Cui Margarita Garcia-Calvo Xin Gu Nancy Kevin Xiuying Ma Lee-yuh Pai Kashmira Shah Xiaolan Shen Sloan Stribling Hratch J. Zokian Joe Metzger Diane E. Shevell Sherman T. Waddell 《Bioorganic & medicinal chemistry letters》2013,23(12):3650-3653
In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11β-HSD1 inhibitors, we examined a set of 11β-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11β-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11β-HSD1 independent pathway. 相似文献
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A transparent nanofibril suspension could be readily obtained by treating purified squid pen powder in water with ultrasonic irradiation. The obtained suspension is consisted of β-chitin nanofibrils (CNF) with 3-10nm in width and several micrometers in length. The degree of acetylation (DA) of CNF was found to be 84% which is about 10% lower than that of untreated sample. The CNF suspension could be transformed into a durable 3-D hydrogels (CH) by simply heating to 180°C for 1-4h in an autoclave. Hydrophobic interaction between CNF was believed to play the major role for CNF self-assembling into hydrogels, since the as-prepared chitin hydrogels readily dissolved in a typical chaotropic solution (8M urea) under room temperature. The hydrothermal duration and CNF concentration (0.3-2% (w/v)) strongly affected the physical properties of CH. The suspension of 1% (w/v) CNF treated with 4h, 180°C hydrothermal heating generated a CH with 99.3% water content, CNF with 87% crystallinity and an mechanical strength of 0.7N breaking force. 相似文献
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Xue Wu Jun Li Xuekang Yang Xiaozhi Bai Jihong Shi Jianxin Gao Yan Li Shichao Han Yijie Zhang Fu Han Yang Liu Xiaoqiang Li Kejia Wang Julei Zhang Zheng Wang Ke Tao Dahai Hu 《Journal of molecular histology》2018,49(4):377-387
Hypertrophic scar (HS) is a serious skin fibrotic disease characterized by the excessive proliferation of fibroblasts and often considered as a kind of benign skin tumor. microRNA-155 (miR-155) is usually served as a promising marker in antitumor therapy. In view of the similarities of hypertrophic scar and tumor, it is predicted that miR-155 may be a novel therapeutic target in clinical trials. Here we found the expression levels of miR-155 was gradually down regulated and HIF-1α was upregulated in HS tissue and HS derived fibroblasts (HFs). And cell proliferation was inhibited when miR-155 was overexpressed or HIF-1α was silenced. Moreover, overexpression of miR-155 in HFs could reduce the expression of collagens in vitro and inhibit the collagen fibers arrangement in vivo, whereas miR-155 knockdown gave opposite results. Furthermore, we found that miR-155 directly targeted the HIF-1α, which could also independently inhibit the expression of collagens in vitro and obviously improved the appearance and architecture of the rabbit ear scar in vivo when it was silencing. Finally, we found that PI3K/AKT pathway was enrolled in these processes. Together, our results indicated that miR-155 was a critical regulator in the formation and development of hypertrophic scar and might be a potential molecular target for hypertrophic scar therapy. 相似文献
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Analysis and use of the perforated patch technique for recording ionic currents in pancreaticβ-cells
Salvador Sala Ramin V. Parsey Akiva S. Cohen Donald R. Matteson 《The Journal of membrane biology》1991,122(2):177-187
Summary To investigate the voltage dependence of the Na–/K– pump, current-voltage relations were determined in prophasearrested oocytes ofXenopus laevis. All solutions contained 5mm Ba2– and 20mm tetraethylammonium (TEA) to block K– channels. If. in addition, the Na+/K+ pump is blocked by ouabain, K+-sensitive currents no larger than 50 nA/cm2 remain. Reductions in steady-state current (on the order of 700 nA/cm2) produced by 50 m ouabain or dihydro-ouabain or by K+ removal, therefore, primarily represent current generated by the Na–/K– pump. In Na–-free solution containing 5mm K+, Na+/K+ pump current is relatively voltage independent over the potential range from –160 to +40 mV. If external [K+] is reduced below 0.5mm, negative slopes are observed over this entire voltage range. Similar results are seen in Na+- and Ca2+-free solutions in the presence of 2mm Ni2+, an experimental condition designed to prevent Na+/Ca2+ exchange. The occurrence of a negative slope can be explained by the voltage dependence of the apparent affinity for activation of the Na+/K+ pump by external K+, consistent with the existence of an external ion well for K– binding. In 90mm Na+, 5mm K+ solution, Na+/K+ pump current-voltage curves at negative membrane potentials have a positive slope and can be described by a monotonically increasing sigmoidal function. At an extracellular [K+] of 1.3mm, a negative slope was observed at positive potentials. These findings suggest that in addition to a voltage-dependent step associated with Na+ translocation, a second voltage-dependent step that is dependent on external [K+], possibly external K+ binding, participates in the overall reaction mechanism of the Na+/K+ pump. 相似文献
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Michael P. Groziak Ronghui Lin William C. Stevens Linda L. Wotring Leroy B. Townsend J. Balzarini 《Nucleosides, nucleotides & nucleic acids》2013,32(5):1041-1057
Abstract ROESY and NOESY NMR spectroscopic analyses of the ribofuranosyl (1a), 2′-deoxyribofuranosyl (1b), and arabinofuranosyl (1c) derivatives of 6-formyluracil in (CD3)2SO and D2O solutions have established that each exclusive 7,05′-cyclic hemiacetal diastereomer of 1a,b and the major 7,O2′-cyclic hemiacetal diastereomer of 1c possess the 7R configuration. In addition, (7R)-1c has been shown to be thermodynamically more stable than (7S)-1c, contrary to our previous indication. A new, higher yielding synthetic route to 1a has been developed, 1b has been obtained for the first time in crystalline form, the route to 1c has been modified to better accommodate large scale preparations, and a new, fourth member of this class, 6-formylthymidine (1d), has been synthesized and its solution structures in (CD3)2SO, D2O, and CD3OD have been determined. Antitumor and antiviral evaluations of 1a-c have revealed no significant levels of activity. 相似文献
10.
Cornelis H. Hokke Jos G. M. van der Ven Johannis P. Kamerling Johannes F. G. Vliegenthart 《Glycoconjugate journal》1993,10(1):82-90
Incubation of synthetic Man\1-4GlcNAc-OMe, GalNAc1-4GlcNAc-OMe, Glc1-4GlcNAc-OMe, and GlcNAc1-4GlcNac-OMe with CMP-Neu5Ac and rat liver Gal1-4GlcNAc (2-6)-sialyltransferase resulted in the formation of Neu5Ac2-6Man1-4GlcNAc-OMe, Neu5Ac2-6GalNAc1-4GlcNAc-OMe, Neu5Ac2-6Glc1-4GlcNAc-OMe and Neu5Ac2-6GlcNAc1-4GlcNAc-OMe, respectively. Under conditions which led to quantitative conversion of Gal1-4GlcNAc-OEt into Neu5Ac2-6Gal1-4GlcNAc-OEt, the aforementioned products were obtained in yields of 4%, 48%, 16% and 8%, respectively. HPLC on Partisil 10 SAX was used to isolate the various sialyltrisaccharides, and identification was carried out using 1- and 2-dimensional 500-MHz1H-NMR spectroscopy.Abbreviations 2D
2-dimensional
- CMP
cytidine 5-monophosphate
- CMP-Neu5Ac
cytidine 5-monophospho--N-acetylneuraminic acid
- COSY
correlation spectroscopy
- DQF
double quantum filtered
- HOHAHA
homonuclear Hartmann-Hahn
- MLEV
composite pulse devised by M. Levitt
- Neu5Ac
N-acetylneuraminic acid
- Neu5Ac2en
2-deoxy-2,3-didehydro-N-acetylneuraminic acid 相似文献
11.
Alexander M Owyang Hassan Issafras John Corbin Kiran Ahluwalia Paul Larsen Elizabeth Pongo Masahisa Handa Arnold H Horwitz Marina K Roell Mary Haak-Frendscho Linda Masat 《MABS-AUSTIN》2011,3(1):49-60
Interleukin-1β (IL-1β) is a potent mediator of inflammatory responses and plays a role in the differentiation of a number of lymphoid cells. In several inflammatory and autoimmune diseases, serum levels of IL-1β are elevated and correlate with disease development and severity. The central role of the IL-1 pathway in several diseases has been validated by inhibitors currently in clinical development or approved by the FDA. However, the need to effectively modulate IL-1β-mediated local inflammation with the systemic delivery of an efficacious, safe and convenient drug still exists. To meet these challenges, we developed XOMA 052 (gevokizumab), a potent anti-IL-1β neutralizing antibody that was designed in silico and humanized using Human Engineering™ technology. XOMA 052 has a 300 femtomolar binding affinity for human IL-1β and an in vitro potency in the low picomolar range. XOMA 052 binds to a unique IL-1β epitope where residues critical for binding have been identified. We have previously reported that XOMA 052 is efficacious in vivo in a diet-induced obesity mouse model thought to be driven by low levels of chronic inflammation. We report here that XOMA 052 also reduces acute inflammation in vivo, neutralizing the effect of exogenously administered human IL-1β and blocking peritonitis in a mouse model of acute gout. Based on its high potency, novel mechanism of action, long half-life and high affinity, XOMA 052 provides a new strategy for the treatment of a number of inflammatory, autoimmune and metabolic diseases in which the role of IL-1β is central to pathogenesis.Key words: IL-1β, gevokizumab, gout, inflammation, autoimmune disease, affinity, therapeutic antibody 相似文献
12.
Häuselmann SP Rosc-Schlüter BI Lorenz V Plaisance I Brink M Pfister O Kuster GM 《Free radical biology & medicine》2011,51(3):609-618
β1-Integrin mediates cardiomyocyte growth and survival and its proper regulation is essential for the structural and functional integrity of the heart. β1-Integrin expression is enhanced in hypertrophy, but the mechanism and significance of its up-regulation are unknown. Because reactive oxygen species (ROS) are important mediators of myocardial remodeling we examined their role in regulated β1-integrin expression. Hypertrophy was induced in neonatal cardiomyocytes by endothelin-1 (ET-1), which activated the regulatory NADPH oxidase subunit Rac1, evoked ROS, and enhanced fetal gene expression and cardiomyocyte size. ET-1 also enhanced cell adhesion and FAK phosphorylation and inhibited oxidative stress-induced cardiomyocyte apoptosis. Further, ET-1 increased β1-integrin mRNA and protein expression via Rac1-ROS-dependent MEK/ERK and EGF receptor-PI3K/Akt activation as shown by adenoviral dominant-negative Rac1 or overexpression of copper/zinc-superoxide dismutase. The relevance of regulated β1-integrin expression was examined in cardiomyocytes, in which targeting siRNA impeded the ET-1-induced β1-integrin up-regulation. In these cells, ET-1-induced cell adhesion, FAK phosphorylation, and hypertrophic response were significantly blunted, whereas its antiapoptotic effect was predominantly unchanged, suggesting at least partial dissociation of prohypertrophic and prosurvival signaling elicited by ET-1. In conclusion, β1-integrin up-regulation in response to ET-1 is mediated via Rac1-ROS-dependent activation of prohypertrophic pathways and is mandatory for ET-1-induced FAK activation, cell adhesion, and hypertrophic response. 相似文献
13.
Kurt G. I. Nilsson 《Biotechnology letters》1996,18(7):791-794
A new approach for the highly specific preparation of L-serine conjugates of lactosamine and Gal1-3GalNAc is described. Thus, the L-serine derivative of lactosamine Gal1-4GlcNAc-O-(N-Z)-Ser-OEt, was obtained from lactose, employing GlcNAc-O-(N-Z)-Ser-OEt as acceptor and a yeast -galactosidase as catalyst Galp 1-3GalNAc-O-(N-Alloc)-Ser-OMe was obtained from lactose, employing GalNAc-O-(N-Alloc)-Ser-OMe as acceptor and -galactosidase from bovine testes as catalyst. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(21):5045-5049
A previous disclosure from this lab highlighted the discovery of pyridyl amides as potent 11β-HSD1 inhibitors. In order to build additional novelty and polarity into this chemotype, replacement of the hydrogen-bonding carbonyl (CO) pharmacophore with the bioisosteric sulfonyl (SO2) group was examined. Despite initial comparisons suggesting the corresponding sulfonamides exhibited weaker activity versus their carbonyl counterparts, further optimization was performed in an effort to identify various potent and unique leads for the program. Judicious incorporation of polar moieties resulted in the identification of compounds with enhanced potency and lipophilicity profiles, resulting in leads with superior aqueous solubility and liver microsomal stability. 相似文献
15.
A domain of epiglucan was synthesized by beta-glucosidases. Two beta-glucosidases, an extracellular beta-glucosidase derived from Sclerotinia sclerotiorum grown on xylose, and a commercial lyophilized preparation of beta-glucosidase from Aspergillus niger, were used to synthesize gluco-oligosaccharides from cellobiose and, specially, beta-(1-6) branched beta-(1-3) gluco-oligosaccharides, corresponding to the structure of epiglucan. Gentiobiose, cellotriose, cellotetraose, beta-Glc-(1-3)-beta-Glc-(1-4)-Glc, beta-Glc-(1-6)-beta-Glc-(1-4)-Glc and beta-Glc-(1-6)-beta-Glc-(1-3)-Glc were synthesized from cellobiose by both enzymes. The latter compound was preferentially synthesized by the beta-glycosidase from Sclerotinia sclerotiorum. Under the best conditions, only 7 g l(-1) of beta-Glc-(1-6)-beta-Glc-(1-3)-Glc was synthesized by the beta-glycosidase from Aspergillus niger compared to 20 g l(-1) synthesized with beta-glycosidase from Sclerotinia sclerotiorum. 相似文献
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John F. Miller Elizabeth M. Turner Ronald G. Sherrill Kristjan Gudmundsson Andrew Spaltenstein Phiroze Sethna Kevin W. Brown Robert Harvey Karen R. Romines Pamela Golden 《Bioorganic & medicinal chemistry letters》2010,20(1):256-259
The identification and optimization of a series of substituted tetrahydro-β-carbolines with potent activity against human papillomavirus is described. Structure–activity studies focused on the substitution pattern and chirality of the β-carboline ring system are discussed. Optimization of these parameters led to compounds with antiviral activities in the low nanomolar range. 相似文献
19.
Ossi Renkonen Ritva Niemelä Anne Leppänen Hannu Maaheimo Antti Seppo Leena Penttilä Anja Vilkman 《Glycoconjugate journal》1991,8(4):368-375
Radiolabelled GlcNAc beta 1-3(GlcNAc beta 1-6)Gal (1), GlcNAc beta 1-3)GlcNAc beta 1-6)Gal beta 1-OCH3 (4), GlcNAc beta 1-3(GlcNAc beta 1-6)Gal beta 1-4Glc (7), and GlcNAc beta 1-3(GlcNAc beta 1-6)Gal beta 1-4GlcNAc (10) were cleaved partially with jack bean beta-N-acetylhexosaminidase (EC 3.2.1.30), and the digests were analysed chromatographically. All four oligosaccharides were hydrolysed faster at the (1-6) branch, than at the (1-3) branch, but a high branch specificity was observed only with the glycan 4. The saccharides 1 and 7 resembled each other in the kinetics of the enzyme-catalysed release of their two non-reducing N-acetylglucosamine units, but the glycan 10 was rather different. The partial digestions made it possible to obtain radiolabelled GlcNAc beta 1-6Gal, GlcNAc beta 1-6Gal beta 1-OCH3, GlcNAc beta 1-6Gal beta 1-4Glc, and, in particular, GlcNAc beta 1-6Gal beta 1-4GlcNAc. 相似文献
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