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51.
52.
Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate 总被引:11,自引:0,他引:11
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Rice R Spencer-Dene B Connor EC Gritli-Linde A McMahon AP Dickson C Thesleff I Rice DP 《The Journal of clinical investigation》2004,113(12):1692-1700
Classical research has suggested that early palate formation develops via epithelial-mesenchymal interactions, and in this study we reveal which signals control this process. Using Fgf10-/-, FGF receptor 2b-/- (Fgfr2b-/-), and Sonic hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by demonstrating that cell proliferation is decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b-/- mice. These results reveal a new role for Fgf signaling in mammalian palate development. We show that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an Fgf-Shh signaling network. 相似文献
53.
Atsushi Ohazama Eric B. Johnson Masato S. Ota Hong J. Choi Thantrira Porntaveetus Shelly Oommen Nobuyuki Itoh Kazuhiro Eto Amel Gritli-Linde Joachim Herz Paul T. Sharpe 《PLoS Clinical Trials》2008,3(12)
The extent to which cell signaling is integrated outside the cell is not currently appreciated. We show that a member of the low-density receptor-related protein family, Lrp4 modulates and integrates Bmp and canonical Wnt signalling during tooth morphogenesis by binding the secreted Bmp antagonist protein Wise. Mouse mutants of Lrp4 and Wise exhibit identical tooth phenotypes that include supernumerary incisors and molars, and fused molars. We propose that the Lrp4/Wise interaction acts as an extracellular integrator of epithelial-mesenchymal cell signaling. Wise, secreted from mesenchyme cells binds to BMP's and also to Lrp4 that is expressed on epithelial cells. This binding then results in the modulation of Wnt activity in the epithelial cells. Thus in this context Wise acts as an extracellular signaling molecule linking two signaling pathways. We further show that a downstream mediator of this integration is the Shh signaling pathway. 相似文献
54.
Ashburn JH Baveja R Kresge N Korneszczuk K Keller S Karaa A Yokoyama Y Zhang JX Huynh T Clemens MG 《Shock (Augusta, Ga.)》2004,22(2):120-130
This study addresses the microvascular mechanisms by which a remote, mild stress such as blunt trauma sensitizes the liver to injury. Rats received closed femur fracture (FFx), and 24 h later livers were isolated and perfused at a similar starting flow rate for assessment of vascular response to endothelin-1 (ET-1). Sinusoidal volumetric flow (QS), red blood cell velocity (VRBC), and sinusoidal diameter (Ds) were determined by intravital microscopy. Baseline portal resistance in livers from FFx rats was not changed. The FFx group showed a lower baseline VRBC (322.9 +/- 26.4 and 207.3 +/- 17.2 microm/s in sham and FFx,) and QS (28.4 +/- 4.2 and 17.6 +/- 2.1 pL/s in sham and FFx, P < 0.05). ET-1 caused a decrease in the VRBC in sham but no change after FFx. In contrast, Ds was unchanged by ET-1 in sham but decreased in FFx (10.3 +/- 0.4 to 10.7 +/- 0.5 vs. 10.6 +/- 0.4 to 9.0 +/- 0.4 microm at 10 min in sham and FFx groups, P < 0.05). The overall result of these changes was a greater decrease in sinusoidal flow in FFx compared with sham. There was no significant change in mRNA for ET-1, endothelin A (ETA) receptor, or iNOS (inducible nitric oxide synthase) in FFx compared with sham. However, endothelin B (ETB) receptor mRNA and eNOS (endothelial nitric oxide synthase) mRNA were increased in the FFx group (ETB, 54.81 +/- 8.08 in sham vs. 83.28 +/- 8.19 in FFx; eNOS, 56.11 +/- 2.53 in sham vs. 83.31 +/- 5.51 in FFx; P < 0.05) while the levels of these proteins remained unchanged. Caveolin-1 (cav-1) protein levels were elevated in FFx, and coimmunoprecipitation with both ETB and eNOS showed increased associations with these proteins, suggesting a possible inactivation of eNOS. The eNOS activity was also blunted in FFx animals in the presence of increased cav-1 expression. Taken together, these results demonstrate that remote trauma sensitizes the liver to the sinusoidal constrictor effect of ET-1. We propose that this hyperresponsiveness occurs as a result of uncoupling of the ETB receptor from eNOS activity mediated by interaction of eNOS and possibly the ETB receptor with increased caveolin-1. This vascular sensitization that occurs after FFx may contribute to the exacerbation of injury during subsequent stresses. 相似文献
55.
56.
Soucek P Kondrova E Hermanek J Stopka P Boumendjel A Ueng YF Gut I 《Anti-cancer drugs》2011,22(2):176-184
Doxorubicin belongs to anthracycline cytotoxic drugs and it is widely used as a major therapeutic agent in the treatment of various types of tumors. However,its therapeutic use is limited by the development of myelosuppression and cardiotoxicity after a specific cumulative dose is reached. The aim of this study was to investigate the effect of flavonoids, either natural or synthetic on doxorubicin-mediated formation of oxidative stress implicated in doxorubicin toxicity. Doxorubicin caused a concentration-dependent increase in the formation of hydroxyl radicals in minipig liver microsomes used as an in-vitro model system. When bacterial membranes heterologously expressing human NADPH cytochrome-P450 oxidoreductase were incubated with doxorubicin, formation of the superoxide radical under aerobic conditions and the doxorubicin–semiquinone radical under anaerobic conditions was detected. Forty different flavonoids were tested for their potency to prevent NADPH-induced or Fe2+-induced peroxidation of lipids in the microsomal system. According to the results, seven flavonoids were selected for evaluation of their potency to inhibit doxorubicin-dependent formation of hydroxyl radicals assessed by electron spin resonance. Myricetin, fisetin, and kaempferol were found to produce a significant protective effect against hydroxyl radicals in the minipig liver microsomal system. In conclusion, this study shows the use of a novel cost-effective in-vitro model system for preselection of antioxidants for testing of their protective effects against toxicity of anthracyclines and potentially other oxidative stress-inducing chemicals. 相似文献
57.
There is evidence that hyperglycemia results in the generation of reactive oxygen species, leading to oxidative stress in various tissues, including vascular system. An important link between oxidative stress, inflammatory response and insulin activity is now well established. The ability of antioxidants to protect against the deleterious effects of hyperglycemia and also to improve glucose metabolism and intake must be considered as leads of choice in diabetes treatment. In addition to their antioxidative activity, many flavonoids were demonstrated to act on biological targets involved in type 2 diabetes mellitus such as: α-glycosidase, glucose cotransporter or aldose reductase. In this context, flavonoids behaving as antioxidants were studied as potential drugs by acting as biological targets involved in diabetes development. In this review, we propose to shed light on antioxidants flavonoids investigated as antidiabetics. A special focus was made to address the structure-activity relationship related to the effect of these naturally occurring molecules on different targets involved in diabetes development. 相似文献
58.
59.
Bougatef K Krichene A Marrakchi R Kourda N Blondeau Lahely Y Moussa A Troudi W Jileni SB Najjar T Soubrier F Ammar Elgaaied AB 《Gastroentérologie clinique et biologique》2007,31(12):1062-1066
Familial Adenomatous Polyposis (FAP) and Attenuated FAP (AFAP) are caused by a germline mutation in the Adenomatous polyposis coli (APC) gene. Recently, a new pathway characterized by a biallelic mutation in the MYH gene, with a recessive model of inheritance was discovered for this inherited syndrome. This report describes a Tunisian patient with an attenuated FAP phenotype, presenting seven colon polyps and an adenocarcinoma but no detectable germline mutations in the FAP target genes. A well known somatic mutation was found in the APC mutation cluster region (MCR). This case shows that further studies are needed to fully understand all the pathways of the FAP syndrome. 相似文献
60.
Rouissi K Ouerhani S Hamrita B Bougatef K Marrakchi R Cherif M Ben Slama MR Bouzouita M Chebil M Ben Ammar Elgaaied A 《Pathology oncology research : POR》2011,17(4):879-886
Cancer epidemiology has undergone marked development since the nineteen-fifties. One of the most spectacular and specific
contributions was the demonstration of the massive effect of smoking and genetic polymorphisms on the occurrence of bladder
cancer. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes, such as the super-families of
N-acetyltransferases (NAT) and glutathione S-transferases (GST). DNA repair is essential to an individual’s ability to respond
to damage caused by tobacco carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual
susceptibility to this environmental exposure. Polymorphisms in NAT2, GST and DNA repair genes alter the ability of these
enzymes to metabolize carcinogens or to repair alterations caused by this process. We have conducted a case-control study
to assess the role of smoking, slow NAT2 variants, GSTM1 and GSTT1 null, and XPC, XPD, XPG nucleotide excision-repair (NER)
genotypes in bladder cancer development in North Tunisia. Taken alone, each gene unless NAT2 did not appear to be a factor
affecting bladder cancer susceptibility. For the NAT2 slow acetylator genotypes, the NAT2*5/*7 diplotype was found to have
a 7-fold increased risk to develop bladder cancer (OR = 7.14; 95% CI: 1.30–51.41). However, in tobacco consumers, we have
shown that Null GSTM1, Wild GSTT1, Slow NAT2, XPC (CC) and XPG (CC) are genetic risk factors for the disease. When combined
together in susceptible individuals compared to protected individuals these risk factors give an elevated OR (OR = 61). So,
we have shown a strong cumulative effect of tobacco and different combinations of studied genetic risk factors which lead
to a great susceptibility to bladder cancer. 相似文献