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61.
GA Bezerra E Dobrovetsky A Dong A Seitova L Crombett LM Shewchuk AM Hassell SM Sweitzer TD Sweitzer PJ McDevitt KO Johanson KM Kennedy-Wilson D Cossar A Bochkarev K Gruber S Dhe-Paganon 《PloS one》2012,7(8):e43019
Proline-specific dipeptidyl peptidases (DPPs) are emerging targets for drug development. DPP4 inhibitors are approved in many countries, and other dipeptidyl peptidases are often referred to as DPP4 activity- and/or structure-homologues (DASH). Members of the DASH family have overlapping substrate specificities, and, even though they share low sequence identity, therapeutic or clinical cross-reactivity is a concern. Here, we report the structure of human DPP7 and its complex with a selective inhibitor Dab-Pip (L-2,4-diaminobutyryl-piperidinamide) and compare it with that of DPP4. Both enzymes share a common catalytic domain (α/β-hydrolase). The catalytic pocket is located in the interior of DPP7, deep inside the cleft between the two domains. Substrates might access the active site via a narrow tunnel. The DPP7 catalytic triad is completely conserved and comprises Ser162, Asp418 and His443 (corresponding to Ser630, Asp708 and His740 in DPP4), while other residues lining the catalytic pockets differ considerably. The "specificity domains" are structurally also completely different exhibiting a β-propeller fold in DPP4 compared to a rare, completely helical fold in DPP7. Comparing the structures of DPP7 and DPP4 allows the design of specific inhibitors and thus the development of less cross-reactive drugs. Furthermore, the reported DPP7 structures shed some light onto the evolutionary relationship of prolyl-specific peptidases through the analysis of the architectural organization of their domains. 相似文献
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64.
Shea-Donohue T Thomas K Cody MJ Aiping Zhao Detolla LJ Kopydlowski KM Fukata M Lira SA Vogel SN 《Innate immunity》2008,14(2):117-124
The role of TLRs and MyD88 in the maintenance of gut integrity in response to dextran sodium sulfate (DSS)-induced colitis was demonstrated recently and led to the conclusion that the innate immune response to luminal commensal flora provides necessary signals that facilitate epithelial repair and permits a return to homeostasis after colonic injury. In this report, we demonstrate that a deficit in a single neutrophil chemokine, CXCL1/KC, also results in a greatly exaggerated response to DSS. Mice with a targeted mutation in the gene that encodes this chemokine responded to 2.5% DSS in their drinking water with significant weight loss, bloody stools, and a complete loss of gut integrity in the proximal and distal colon, accompanied by a predominantly mononuclear infiltrate, with few detectable neutrophils. In contrast, CXCL1/KC(- /-) and wild-type C57BL/6J mice provided water showed no signs of inflammation and, at this concentration of DSS, wild-type mice showed only minimal histopathology, but significantly more infiltrating neutrophils. This finding implies that neutrophil infiltration induced by CXCL1/KC is an essential component of the intestinal response to inflammatory stimuli as well as the ability of the intestine to restore mucosal barrier integrity. 相似文献
65.
Laubitz D Larmonier CB Bai A Midura-Kiela MT Lipko MA Thurston RD Kiela PR Ghishan FK 《American journal of physiology. Gastrointestinal and liver physiology》2008,295(1):G63-G77
Na+/H+ exchanger 3 (NHE3) provides a major route for intestinal Na+ absorption. NHE3 has been considered a target of proinflammatory cytokines and enteropathogenic bacteria, and impaired NHE3 expression and/or activity may be responsible for inflammation-associated diarrhea. However, the possibility of loss of NHE3 function reciprocally affecting gut immune homeostasis has not been investigated. In this report, we describe that NHE3-deficient mice spontaneously develop colitis restricted to distal colonic mucosa. NHE3(-/-) mice housed in a conventional facility exhibited phenotypic features such as mild diarrhea, occasional rectal prolapse, and reduced body weight. Genomewide microarray analysis identified not only a large group of transport genes that potentially represent an adaptive response, but also a considerable number of genes consistent with an inflammatory response. Histological examination demonstrated changes in the distal colon consistent with active inflammation, including crypt hyperplasia with an increased number of 5-bromo-2'-deoxyuridine-positive cells, diffuse neutrophilic infiltrate with concomitant 15-fold increase in matrix metalloproteinase 8 expression, an increased number of pSer276-RelA-positive cells, and a significant decrease in periodic acid-Schiff-positive goblet cells. Real-time PCR demonstrated elevated expression of inducible nitric oxide synthase (38-fold), TNF-alpha (6-fold), macrophage inflammatory protein-2 (48-fold), and IL-18 (3-fold) in the distal colon of NHE3(-/-) mice. NHE3(-/-) mice showed enhanced bacterial adhesion and translocation in the distal colon. Colitis was ameliorated by oral administration of broad-spectrum antibiotics. In conclusion, NHE3 deficiency leads to an exacerbated innate immune response, an observation suggesting a potentially novel role of NHE3 as a modifier gene, which when downregulated during infectious or chronic colitis may modulate the extent and severity of colonic inflammation. 相似文献
66.
Proteomic analysis of cervical cancer cells treated with suberonylanilide hydroxamic acid 总被引:1,自引:0,他引:1
Jianxiong He Canhua Huang Aiping Tong Bin Chen Zhi Zeng Peng Zhang Chunting Wang Yuquan Wei 《Journal of biosciences》2008,33(5):715-721
Suberonylanilide hydroxamic acid (SAHA) is an orally administered histone deacetylase inhibitor (HDACI) that has shown significant
antitumour activity in a variety of tumour cells. To identify proteins involved in its antitumour activity, we utilized a
proteomic approach to reveal protein expression changes in the human cervical cancer cell line HeLa following SAHA treatment.
Protein expression profiles were analysed by 2-dimensional polyacrylamide gel electrophoresis (2-DE) and protein identification
was performed on a MALDI-Q-TOF MS/MS instrument. As a result, a total of nine differentially expressed proteins were visualized
by 2-DE and Coomassie brilliant blue (CBB) staining. Further, all the changed proteins were positively identified via mass
spectrometry (MS)/MS analysis. Of these, PGAM1 was significantly downregulated in HeLa cells after treatment with SAHA. Moreover,
PGAM1 has been proven to be downregulated in another cervical cancer cell line (CaSki) by western blot analysis. Together,
using proteomic tools, we identified several differentially expressed proteins that underwent SAHA-induced apoptosis. These
changed proteins may provide some clues to a better understanding of the molecular mechanisms underlying SAHA-induced apoptosis
in cervical cancer. 相似文献
67.
几种控释氮肥减少氨挥发的效果及影响因素研究 总被引:25,自引:4,他引:21
采用“静态吸收法”和“土柱淋溶法”、室内模拟试验,研究几种控释氮肥施入土壤后的氨挥发损失情况、N溶出速率、土壤脲酶活性及pH值变化的关系.结果表明,施氮450mg·kg^-1土时,3种控释氮肥氨挥发损失氮总量分别比普通尿素减少49.7%、28.0%和71.2%;施氮600mg·kg^-1土时,3种控释氮肥氨挥发损失氮总量分别比普通尿素减少34.6%、12.3%和69.9%.控释氮肥能显著降低土壤氨挥发量,减少因施肥而引起的大气环境污染.控释氮肥氨挥发量与不同氮肥引起的土壤脲酶活性、pH值、土壤中氮溶出速率密切相关.土壤的氨挥发总量与肥料在土壤中溶出总量的相关系数达到0.9533,在肥料施入的前期土壤氨挥发量同土壤脲酶活性、pH值的相关系数达到0.9533和0.9908。 相似文献
68.
N-myc downstream-regulated genes 1 and 3 (NDRG1 and NDRG3) are members of the alpha/beta hydrolase superfamily. Phylogenetic analysis of the family demonstrated that human NDRG1 and 3 belong to a subfamily. The mapping and gene expression patterns of these genes represent one step toward further investigation into their possible roles in the chicken (Gallus gallus). To map these genes in the chicken chromosome, a 6000 rads chicken-hamster radiation hybrid panel (ChickRH6) was used. Primers were designed according to the published human sequences for amplification of those two genes. We compared the corresponding human mRNA sequences with the predicted coding sequences of the chicken NDRG1 and 3 genes and found that the assembled contigs shared a high percentage of similarity with the human genes. PCR of samples from ChickRH6 revealed that the locations of NDRG1 and 3 are linked to the markers MYC (58 cRs away, LOD score 4.52) and SEQ0265 (10 cRs away, LOD score 17.81), respectively. This result adds two new markers to the chicken RH map, and it reinforces that the RH technique is indeed a powerful tool for mapping genes due to its rapidity, precision, convenience, and reproducibility. In addition, we detected the gene expression and distribution of chicken NDRG1 and 3 in seven tissues, including heart, liver, spleen, lung, muscle, brain, and thymus, by RT-PCR, and found that NDRG1 is relatively ubiquitously expressed in all the tested tissues and highly expressed in heart and liver, whereas NDRG3 is high in heart, muscle, and brain. 相似文献
69.
Yao-Song Gui Lianmei Wang Xinlun Tian Ruie Feng Aiping Ma Baiqiang Cai Hongbing Zhang Kai-Feng Xu 《PloS one》2012,7(9)
Although several Cre-loxP-based gene knockout mouse models have been generated for the study of gene function in alveolar epithelia in the lung, their applications are still limited. In this study, we developed a SPC-Cre-ERT2 mouse model, in which a tamoxifen-inducible Cre recombinase (Cre-ERT2) is under the control of the human surfactant protein C (SPC) promoter. The specificity and efficiency of Cre-ERT2 activity was first evaluated by crossing SPC-Cre-ERT2 mouse with ROSA26R mouse, a β-galactosidase reporter strain. We found that Cre-ERT2 was expressed in 30.7% type II alveolar epithelial cells of SPC-Cre-ERT2/ROSA26R mouse lung tissues in the presence of tamoxifen. We then tested the tamoxifen-inducible recombinase activity of Cre-ERT2 in a mouse strain bearing TSC1 conditional knockout alleles (TSC1fx/fx). TSC1 deletion was detected in the lungs of tamoxifen treated SPC-Cre-ERT2/TSC1fx/fx mice. Therefore this SPC-Cre-ERT2 mouse model may be a valuable tool to investigate functions of genes in lung development, physiology and disease. 相似文献
70.
Di Lu Yang An Simin Feng Xiaodan Li Aiping Fan Zheng Wang Yanjun Zhao 《AAPS PharmSciTech》2018,19(6):2610-2619
The complex design of multifunctional nanomedicine is beneficial to overcome the multiple biological barriers of drug delivery, but it also presents additional hurdles to clinical translation (e.g., scaling-up and quality control). To address this dilemma, we employed a simple imidazole-bearing polymer micelle for enhanced cellular uptake, facilitated endosomal escape, and on-demand release of a model drug, SN-38. The micelles were crosslinked by the reversible imidazole/Zn2+ coordination with a drug loading of ca. 4% (w/w) and a diameter less than 200 nm. Under mimicked tumor microenvironment (pH 6.8), the surface charge of micelles reversed from negative to positive, leading to enhanced micelles uptake by model 4T1 cells. Such effect was verified by fluorescent labelling of micelles. Compared to imidazole-free nanocarriers, the charge-reversal micelles delivered significantly more SN-38 to 4T1 cells. Due to the proton sponge effect, imidazole-bearing micelles could rapidly escape from endosomes compared to the control micelles, as evidenced by the kinetic analysis of micelle/endosome co-localization. The coordination crosslinking also enabled the acid-triggered drug release. This work provides a “three birds with one stone” approach to achieve the multifunctionality of nanocarriers without complicated particle design, and opens new avenues of advancing nanomedicine translation via simple tailored nanocarriers. 相似文献