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ABSTRACT: Cryptotanshinone (CTS), a major constituent extracted from the medicinal herb Salvia miltiorrhiza Bunge, has well-documented antioxidative and anti-inflammatory effects. In the present study, the pharmacological effects and underlying molecular mechanisms of CTS on lipopolysaccharide (LPS)-induced inflammatory responses were investigated. By enzyme-linked immunosorbent assay, we observed that CTS reduced significantly the production of proinflammatory mediators (tumor necrosis factor-α and interleukin-6) induced by LPS in murine macrophage-like RAW264.7 cells. Mechanistically, CTS inhibited markedly the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, p38MAPK, and JNK, which are crucially involved in regulation of proinflammatory mediator secretion. Moreover, immunofluorescence and western blot analysis indicated that CTS abolished completely LPS-triggered nuclear factor-κB (NF-κB) activation. Taken together, these data implied that NF-κB and MAPKs might be the potential molecular targets for clarifying the protective effects of CTS on LPS-induced inflammatory cytokine production in macrophages.
Inflammation 04/2011; 34(2):111-8. · 1.75 Impact Factor
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ABSTRACT: Angiotensin II (Ang II)-induced hypertrophy response in cultured cardiomyocytes is partially mediated by endothelin-1 (ET-1). Endothelin converting enzyme-1 (ECE-1) is the rate limiting enzyme in the process of ET-1 production. In this study, two peptides which have significant inhibitory effect to the activity of rat ECE-1 purified from stable rat ECE-1-expressed CHO lines, were selected from 13 big ET-1 analogues. We found that treatment of P8 or P9 reversed the increase of hypertrophy genetic markers and cell surface area in primary cultured neonatal rat cardiomyocytes stimulated by Ang II. Besides, depletion of ECE-1 by RNA interference also revealed similar results as P8 or P9 treatment. These results confirmed that ECE-1 plays a key role in regulating Ang II-induced hypertrophy response in cultured cardiomyocytes.
Pharmazie 11/2009; 64(11):755-9. · 1.01 Impact Factor
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ABSTRACT: Tumour necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine, which has been shown to be a causative factor in rheumatoid arthritis, inflammatory bowel disease and septic shock. Proinflammatory effect of TNF-alpha is activated mainly through human TNF receptor-1 (TNF-R1). However, the role of the fourth cystein-rich domain (CRD4) of TNF-R1 extracellular portion in the interaction of TNF-alpha with TNF-R1 is still unclear. In the present study, binding activity of TNF-alpha to TNF-R1 and protein levels of IkappaB-alpha and nuclear transcription factor kappa B (NF-kappaB) p65 subunit in HeLa cells were measured using enzyme-linked immunosorbent assay (ELISA) and western-blot analysis. Pep 3 (LRENECVS) which was derived from the hydrophilic region of A1 module in CRD4 remarkably inhibited the binding of TNF-alpha to TNF-R1, and also reversed TNF-alpha-induced degradation of IkappaB-alpha and nuclear translocation of NF-kappaB p65 subunit in HeLa cells. Our results confirmed that the hydrophilic region of A1 module in CRD4 participated in the interaction of TNF-alpha with TNF-R1, and demonstrated the potential of small-molecule TNF-alpha extracellular inhibitors targeting at A1 module in CRD4 of TNF-R1 in suppressing proinflammatory effect of TNF-alpha.
Inflammation 04/2009; 32(3):139-45. · 1.75 Impact Factor
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Zhengrong Mei,
Fangyan Zhang,
Liang Tao,
Wenhua Zheng,
Yingnan Cao,
Zhaohe Wang, Shu Tang,
Kang Le,
Shaorui Chen,
Rongbiao Pi,
Peiqing Liu
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ABSTRACT: The amyloid precursor protein (APP) is cleaved enzymatically by non-amyloidogenic and amyloidogenic pathways. alpha-Secretase cleaves APP within beta-amyloid protein (Abeta) sequence, resulting in the release of a secreted fragment of APP (sAPPalpha) and precluding Abeta generation. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of Alzheimer's disease (AD). However, the effects of CTS on the Abeta plaque pathology and the APP processing in AD are unclear. Here we reported that CTS strongly attenuated amyloid plaque deposition in the brain of APP/PS1 transgenic mice. In addition, CTS significantly improved spatial learning and memory in APP/PS1 mice assessed by the Morris water maze testing. To define the exact molecular mechanisms involved in the beneficial effects of CTS, we investigated the effects of the CTS on APP processing in rat cortical neuronal cells overexpressing Swedish mutant human APP695. CTS was found to decrease Abeta generation in concentration-dependent (0-10muM) manner. Interestingly, the N-terminal APP cleavage product, sAPPalpha was markedly increased by CTS. Further study showed that alpha-secretase activity was increased by CTS. Taken together, our results suggested CTS improved the cognitive ability in AD transgenic mice and promoted APP metabolism toward the non-amyloidogenic products pathway in rat cortical neuronal cells. CTS shows a promising novel way for the therapy of AD.
Neuroscience Letters 02/2009; 452(2):90-5. · 2.11 Impact Factor
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ABSTRACT: The identification of transcription factors that regulate the transcription of the fibroblast growth factor-2 (FGF-2) gene has facilitated the understanding of the etiology of cardiovascular diseases. The purpose of this study was to determine the molecular mechanism underlying the activation of FGF-2 gene transcription in cardiomyocytes from neonatal rats.
To identify the factors involved in cardiac expression of FGF-2, we used transient transfections in neonatal rat cardiomyocytes coupled with electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) analyses.
Deletion analyses showed that the region between -16 and +59 was essential for maximal FGF-2 promoter activity. Three putative stimulating protein 1 (Sp1) regulatory sites located at positions -3, +14, and +27 were predicted within this region by computer analysis. EMSA showed the existence of two atypical G-rich Sp1-binding elements located at positions -3 and +14. Mutation of these two sites resulted in a significant decline in FGF-2 promoter activity compared to wild type promoter activity. Combinatorial mutation of these sites reduced the promoter activity to background levels. Mutation of the Sp1 motif at +27 did not affect promoter activity. Lastly, ChIP analyses revealed that Sp1 binds to the FGF-2 promoter region in vivo.
These results indicate that expression of FGF-2 in neonatal rat cardiomyocytes is associated with Sp1 binding to the FGF-2 promoter.
Life sciences 02/2009; 84(13-14):421-7. · 2.56 Impact Factor
