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221.
The aim of this study was to explore the association of MMP-2 (-1306 C/T and -168 G/T) and MMP-9 (-1562 C/T) promoter polymorphisms in oral submucous fibrosis (OSMF) and head and neck squamous cell carcinoma (HNSCC) cases. These SNP were genotyped by PCR-RFLP. Total of 1260 individuals were recruited, of which 412 OSMF, 422 HNSCC and 426 were controls. In HNSCC, MMP-2 (-1306 C/T) and MMP-9 (-1562C/T) polymorphism, T allele showed strong association (p < 0.00 and p < 0.01) as compared to healthy control respectively, but not in case of OSMF and showed significant association with increasing progression of clinico-pathological grading. We concluded that SNPs in the MMP-2 and -9 promoter region may be associated with susceptibility to HNSCC not in OSMF.  相似文献   
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Achieving both, nontoxicity and stability in antimicrobial peptides (AMP) is a challenge. This study predicts a structurally stable, nontoxic scaffold among the protegrin family, for future therapeutic peptide analogs. Protegrins (PG) are a class of pharmaceutically approved, in demand AMPs, which require further improvement in terms of nontoxicity and stability. Out of five protegrins viz., PG1, PG2, PG3, PG4 and PG5, PG1 has been predicted as best scaffold. Prediction was based upon sequential elimination of other protegrins, using computational methods to assess the extracellular bacterial membrane penetrability, nontoxicity and structural stability by geometric observables. Initially, PG2 and PG4 showing the lowest membrane penetrability and highest toxicity respectively, were screened out. Among the remaining three protegrins, PG1 displayed both lowest root mean square deviation and radius of gyration, with a considerable occupancy of seven H-bonds and established uniform secondary structure profile throughout its ensembles. Therefore, the authors claim the superiority of PG1 as a nontoxic stable scaffold among its family.

Communicated by Ramaswamy H. Sarma  相似文献   

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BackgroundThere is growing evidence to support beneficial effects of the hypothalamic synthesised hormone, oxytocin, on metabolism. However, the biological half-life of oxytocin is short and receptor activation profile unspecific.MethodsWe have characterised peptide-based oxytocin analogues with structural modifications aimed at improving half-life and receptor specificity. Following extensive in vitro and in vivo characterisation, antidiabetic efficacy of lead peptides was examined in high fat fed (HFF) mice.ResultsFollowing assessment of stability against enzymatic degradation, insulin secretory activity, receptor activation profile and in vivo bioactivity, analogues 2 N (Ac-C ?YIQNC >PLG-NH2) and D7R ((d-C)YIQNCYLG-NH2) were selected as lead peptides. Twice daily injection of either peptide for 22 days reduced body weight, energy intake, plasma glucose and insulin and pancreatic glucagon content in HFF mice. In addition, both peptides reduced total- and LDL-cholesterol, with concomitant elevations of HDL-cholesterol, and D7R also decreased triglyceride levels. The two oxytocin analogues improved glucose tolerance and insulin responses to intraperitoneal, and particularly oral, glucose challenge on day 22. Both oxytocin analogues enhanced insulin sensitivity, reduced HOMA-IR and increased bone mineral density. In terms of pancreatic islet histology, D7R reversed high fat feeding induced elevations of islet and beta cell areas, which was associated with reductions in beta cell apoptosis. Islet insulin secretory responsiveness was improved by 2 N, and especially D7R, treatment.ConclusionNovel, enzymatically stable oxytocin analogues exert beneficial antidiabetic effects in HFF mice.General significanceThese observations emphasise the, yet untapped, therapeutic potential of long-acting oxytocin-based agents for obesity and type 2 diabetes.  相似文献   
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The receptor tyrosine kinase c-Kit, also known as the stem cell factor receptor, plays a key role in several developmental processes. Activating mutations in c-Kit lead to alteration of these cellular processes and have been implicated in many human cancers such as gastrointestinal stromal tumors, acute myeloid leukemia, testicular seminomas and mastocytosis. Regulation of the catalytic activity of several kinases is known to be governed by phosphorylation of tyrosine residues in the activation loop of the kinase domain. However, in the case of c-Kit phosphorylation of Tyr-823 has been demonstrated to be a late event that is not required for kinase activation. However, because phosphorylation of Tyr-823 is a ligand-activated event, we sought to investigate the functional consequences of Tyr-823 phosphorylation. By using a tyrosine-to-phenylalanine mutant of tyrosine 823, we investigated the impact of Tyr-823 on c-Kit signaling. We demonstrate here that Tyr-823 is crucial for cell survival and proliferation and that mutation of Tyr-823 to phenylalanine leads to decreased sustained phosphorylation and ubiquitination of c-Kit as compared with the wild-type receptor. Furthermore, the mutated receptor was, upon ligand-stimulation, quickly internalized and degraded. Phosphorylation of the E3 ubiquitin ligase Cbl was transient, followed by a substantial reduction in phosphorylation of downstream signaling molecules such as Akt, Erk, p38, Shc, and Gab2. Thus, we propose that activation loop tyrosine 823 is crucial for activation of both the MAPK and PI3K pathways and that its disruption leads to a destabilization of the c-Kit receptor and decreased survival of cells.  相似文献   
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Metronidazole (MNZ), the first line drug for amoebiasis and auranofin (AF), an emerging antiprotozoan drug, are both inhibiting Entamoeba histolytica thioredoxin reductase. The nature of oxidised proteins (OXs) formed in AF‐ or MNZ‐treated E. histolytica trophozoites is unknown. In order to fill this knowledge gap, we performed a large‐scale identification and quantification of the OXs formed in AF‐ or MNZ‐treated E. histolytica trophozoites using resin‐assisted capture coupled to mass spectrometry (MS). We detected 661 OXs in MNZ‐treated trophozoites and 583 OXs in AF‐treated trophozoites. More than 50% of these OXs were shared, and their functions include hydrolases, enzyme modulators, transferases, nucleic acid binding proteins, oxidoreductases, cytoskeletal proteins, chaperones, and ligases. Here, we report that the formation of actin filaments (F‐actin) is impaired in AF‐treated trophozoites. Consequently, their erythrophagocytosis, cytopathic activity, and their motility are impaired. We also observed that less than 15% of OXs present in H2O2‐treated trophozoites are also present in AF‐ or MNZ‐treated trophozoites. These results strongly suggest that the formation of OXs in AF‐ or MNZ‐treated trophozoites and in H2O2‐treated trophozoites occurred by two different mechanisms.  相似文献   
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A simple, sensitive and specific LC-MS/MS method for the simultaneous determination of sulforaphane (SFN) and its major metabolites, the glutathione (SFN-GSH) and N-acetyl cysteine conjugates (SFN-NAC) from biological matrices was developed and validated. The assay procedure involved solid-phase extratcion of all three analytes from rat intestinal perfusate using C2 extraction cartridges, whereas from rat plasma, metabolites were extracted by solid-phase extraction and SFN was extracted by liquid-liquid extraction with ethyl acetate. Chromatographic separation of SFN, SFN-GSH and SFN-NAC was achieved on a C8 reverse phase column with a mobile phase gradient (Mobile Phase A: 10mM ammonium acetate buffer, pH: 4.5 and Mobile Phase B: acetonitrile with 0.1% formic acid) at a flow rate of 0.3 mL/min. The Finnigan LCQ LC-MS/MS was operated under the selective reaction monitoring mode using the electrospray ionization technique in positive mode. The nominal retention times for SFN-GSH, SFN-NAC and SFN were 8.4, 11.0, and 28.2 min,, respectively. The method was linear for SFN and its metabolites with correlation coefficients >0.998 for all analytes. The limit of quantification was 0.01-0.1 microm depending on analyte and matrix, whereas the mean recoveries from spiked plasma and perfusate samples were approximately 90%. The method was further validated according to U.S. Food and Drug Administration guidance in terms of accuracy and precision. Stability of compounds was established in a battery of stability studies, i.e., bench top, auto-sampler and long-term storage stability as well as freeze/thaw cycles. The utility of the assay was confirmed by the analysis of intestinal perfusate and plasma samples from single-pass intestinal perfusion studies with mesenteric vein cannulation in rats.  相似文献   
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Zinc is the second-most abundant transition metal within cells and an essential micronutrient. Although adequate zinc is essential for cellular function, intracellular free zinc (Zn2+) is tightly controlled, as sustained increases in free Zn2+ levels can directly contribute to apoptotic endothelial cell death. Moreover, exposure of endothelial cells to acute nitrosative and/or oxidative stress induces a rapid rise of Zn2+ with mitochondrial dysfunction and the initiation of apoptosis. This apoptotic induction can be mimicked through addition of exogenous ZnCl2 and mitigated by zinc-chelation strategies, indicating Zn2+-dependent mechanisms in this process. However, the molecular mechanisms of Zn2+-mediated mitochondrial dysfunction are unknown. Here we report that free Zn2+ disrupts cellular redox status through inhibition of glutathione reductase, and induces apoptosis by redox-mediated inhibition of the mitochondrial adenine nucleotide transporter (ANT). Inhibition of ANT causes increased mitochondrial oxidation, loss of ADP uptake, mitochondrial translocation of bax, and apoptosis. Interestingly, pre-incubation with glutathione ethyl ester protects endothelial cells from these observed effects. We conclude that key mechanisms of Zn2+-mediated apoptotic induction include disruption of cellular glutathione homeostasis leading to ANT inhibition and decreases in mitochondrial ATP synthesis. These pathways could represent novel therapeutic targets during acute oxidative or nitrosative stress in cells and tissues.  相似文献   
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