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61.
Screen M Britton M Downey SL Verdoes M Voges MJ Blom AE Geurink PP Risseeuw MD Florea BI van der Linden WA Pletnev AA Overkleeft HS Kisselev AF 《The Journal of biological chemistry》2010,285(51):40125-40134
Proteasomes degrade most proteins in mammalian cells and are established targets of anti-cancer drugs. The majority of proteasome inhibitors are composed of short peptides with an electrophilic functionality (pharmacophore) at the C terminus. All eukaryotic proteasomes have three types of active sites as follows: chymotrypsin-like, trypsin-like, and caspase-like. It is widely believed that active site specificity of inhibitors is determined primarily by the peptide sequence and not the pharmacophore. Here, we report that active site specificity of inhibitors can also be tuned by the chemical nature of the pharmacophore. Specifically, replacement of the epoxyketone by vinyl sulfone moieties further improves the selectivity of β5-specific inhibitors NC-005, YU-101, and PR-171 (carfilzomib). This increase in specificity is likely the basis of the decreased cytotoxicity of vinyl sulfone-based inhibitors to HeLa cells as compared with that of epoxyketone-based inhibitors. 相似文献
62.
Rheal A. Towner Nataliya Smith Sabrina Doblas Philippe Garteiser Yasuko Watanabe Ting He Debra Saunders Oana Herlea Robert Silasi-Mansat Florea Lupu 《Free radical biology & medicine》2010,48(5):691-703
Increased iNOS expression is often found in brain tumors, such as gliomas. The goal of this study was to develop and assess a novel molecular MRI (mMRI) probe for in vivo detection of iNOS in rodent models for gliomas (intracerebral implantation of rat C6 or RG2 cells or ethyl nitrosourea-induced glioma). The probe we used incorporated a Gd-DTPA (gadolinium(III) complex of diethylenetriamine-N,N,N′,N″,N″-pentaacetate) backbone with albumin and biotin moieties and covalent binding of an anti-iNOS antibody (Ab) to albumin (anti-iNOS probe). We used mMRI with the anti-iNOS probe to detect in vivo iNOS levels in gliomas. Nonimmune normal rat IgG coupled to albumin–Gd-DTPA–biotin was used as a control nonspecific contrast agent. By targeting the biotin component of the anti-iNOS probe with streptavidin Cy3, fluorescence imaging confirmed the specificity of the probe for iNOS in glioma tissue. iNOS levels in glioma tumors were also confirmed via Western blots and immunohistochemistry. The presence of plasma membrane-associated iNOS in glioma cells was established by transmission electron microscopy and gold-labeled anti-iNOS Ab. The more aggressive RG2 glioma was not found to have higher levels of iNOS compared to C6. Differences in glioma vascularization and blood–brain barrier permeability between the C6 and the RG2 gliomas are discussed. In vivo assessment of iNOS levels associated with tumor development is quite feasible in heterogeneous tissues with mMRI. 相似文献
63.
We previously characterized VE-statin/egfl7, a protein that is exclusively secreted by endothelial cells and modulates smooth muscle cell migration. Here, we show that VE-statin/egfl7 is the first known natural negative regulator of vascular elastogenesis. Transgenic mice, expressing VE-statin/egfl7 under the control of keratin-14 promoter, showed an accumulation of VE-statin/egfl7 in arterial walls where its presence correlated with an impaired organization of elastic fibres. In vitro, fibroblasts cultured in the presence of VE-statin/egfl7 were unable to deposit elastic fibres due to a deficient conversion of soluble tropoelastin into insoluble mature elastin. VE-statin/egfl7 interacts with the catalytic domain of lysyl oxidase (LOX) enzymes and, in endothelial cells, endogenous VE-statin/egfl7 colocalizes with LoxL2 and inhibits elastic fibre deposition. In contrast, mature elastic fibres are abundantly deposited by endothelial cells that are prevented from producing endogenous VE-statin/egfl7. We propose a model where VE-statin/egfl7 produced by endothelial cells binds to the catalytic domains of enzymes of the LOX family in the vascular wall, thereby preventing the crosslink of tropoelastin molecules into mature elastin polymers and regulating vascular elastogenesis. 相似文献
64.
Eduardo AVF Ramalho Jo?o LQ Silva-Filho Marina FS Cartaxo Carmelita BL Cavalcanti Moacyr JBM Rêgo Maria BM Oliveira Eduardo IC Beltr?o 《Biological research》2014,47(1)
Background
BRCA protein interacts with at least 13 different proteins that have been implicated with cancer susceptibility and loss of BRCA function is correlated to sensitivity to DNA crosslinking agents in preclinical models.Results
BRCA2 methylation frequency was 44%, p53 Pro22 allele frequency was 32% and heterozygous frequency of Arg/Pro72 genotype was 60% which could be associated as risk factor for metastasis (p = 0.046 OR = 4.190). Regarding to polymorphism of codon 249 the frequency of Arg249 allele presented 82% which was considered not statistically significant.Conclusions
There was not statistical significance to BRCA2 promoter methylation with any parameters chosen. However, our findings suggest that patients who present heterozygous genotype at codon 72 of p53 gene may have a major susceptibility to any type of metastasis and this could serve as potential auxiliary biomarker for poor prognosis. 相似文献65.
Florea C Usein CR Condei M Damian M 《Roumanian archives of microbiology and immunology》2007,66(1-2):41-43
The urinary tract is among the most common sites of bacterial infection and E. coli is by far the most common infecting agent in children and adults of both sexes. In an attempt to evaluate the intrinsic virulence of E. coli uroisolates from children, 54 strains were assessed by using PCR for the presence of five representative genetic determinants coding for adherence systems (pap, sfa/foc, afa), and toxins (hly and cnf). The prevalence of pap, sfa/foc and afa genes was 55%, 54%, and 44%, respectively. Hemolysin-encoding gene hly was detected in 55% strains, while cnf was exhibited by 35% of the screened E. coli isolates. Among the 39 PCR positive strains isolated from children's urine cultures the co-occurrence of the various targeted virulence genes was detected in 30 strains, the virulence profiles identified suggesting the presence of their localization on chromosomal regions known as pathogencity-associated islands. The rapid and reliable detection of the intrinsic virulence potential by this molecular approach could be very useful when evaluating the importance of microorganism pathogenicity versus host's susceptibility for developing an overt symptomatology of infection. 相似文献
66.
Towner RA Smith N Tesiram YA Abbott A Saunders D Blindauer R Herlea O Silasi-Mansat R Lupu F 《Molecular imaging》2007,6(1):18-29
The multifunctional growth factor scatter factor/hepatocyte growth factor and its tyrosine kinase receptor, c-MET, have been implicated in the genesis and malignant progression of numerous human malignancies, including hepatocellular carcinomas. The incidence of hepatocellular carcinomas in the United States has increased noticeably over the past two decades and is listed as the fifth major cancer in men worldwide. In this study, we used a choline-deficient l-amino acid (CDAA)-defined rat hepatocarcinogenesis model to visualize increased in vivo expression of the c-MET antigen in neoplastic lesion formation with the use of a super paramagnetic iron oxide (SPIO)-anti-c-MET molecularly targeted magnetic resonance imaging (MRI) contrast agent. SPIO-anti-c-MET was used for the first time to detect overexpression of c-MET in neoplastic nodules and tumors within the livers of CDAA-treated rats, as determined by a decrease in MRI signal intensity and a decrease in regional T(2) values. Specificity for the binding of the molecularly targeted anti-c-MET contrast agent was determined using rat hepatoma (H4-II-E-C3) cell cultures and immunofluorescence microscopic imaging of the targeting agents within neoplastic liver tissue 1 to 2 hours following intravenous administration of SPIO-anti-c-MET and MRI investigation. This method has the ability to visualize in vivo the overexpression of c-MET at early developmental stages of tumor formation. 相似文献
67.
Aikaterini Skorda Aimilia D. Sklirou Theodore Sakellaropoulos Despoina D. Gianniou Efstathios Kastritis Evangelos Terpos Ourania E. Tsitsilonis Bogdan I. Florea Herman S. Overkleeft Meletios A. Dimopoulos Leonidas G. Alexopoulos Ioannis P. Trougakos 《Journal of cellular and molecular medicine》2019,23(12):8010-8018
Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle‐cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non‐lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib‐like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non‐lethal (IC10) doses of the PIs revealed inhibitor‐ and cell type‐specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro‐tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro‐tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse. 相似文献
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69.
We review our baboon models of Escherichia coli sepsis that mimic, respectively, the shock/disseminated intravascular coagulation (DIC) and organ failure variants of severe sepsis, and analyse the pathophysiologic processes that are unique to each. The multi-stage, multi-factorial characteristics of severe sepsis develop as a result of the initial insult, which - depending on its intensity - activates components of the intravascular compartment leading to overwhelming shock/DIC; or initiates a sequence of events involving both the intra- and extravascular (tissues) compartments that lead to organ failure. In the latter case, the disorder passes through two stages: an initial inflammatory/coagulopathic intravascular first stage triggered by E. coli, followed by an extravascular second stage, involving components unique to each organ and triggered by ischemia/reperfusion (oxidative stress and histone release). Although a myriad of overlapping cellular and molecular components are involved, it is the context in which these components are brought into play that determine whether shock/DIC or organ failure predominate. For example, inflammatory and thrombotic responses amplified by thrombin in the first case whereas similar responses are amplified by complement activation products in the second. Rather than blocking specific mediators, we found that attenuation of the thrombin and complement amplification pathways can effectively reverse the shock/DIC and organ failure exhibited by the LD(100) and LD(50) E. coli models of severe sepsis, respectively. Translation of these concepts to successful intervention in the respective baboon models of E. coli sepsis and the application to their clinical counterparts is described. 相似文献
70.
Christopher L. Schardl Carolyn A. Young Jerome R. Faulkner Simona Florea Juan Pan 《Fungal Ecology》2012,5(3):331-344
The epichloid fungi – comprising sexual Epichloë species and asexual Neotyphodium species – are symbionts of cool-season grasses (subfamily Poöideae), mostly vertically transmissible (seedborne), and well known for production of anti-herbivore alkaloids. Four classes of alkaloids are known to be produced by epichloae: lolines (saturated aminopyrrolizidines), indole–diterpenes, ergot alkaloids, and peramine. There is a wide range of chemotypic diversity among and even within epichloid species. At the molecular level, this diversity may in part reflect the telomeric association of two of the four alkaloid biosynthesis gene clusters. Ecologically, the chemotypic diversity within species may reflect frequency-dependent selection for the alkaloids, which provide defences against insects and, in some cases, vertebrates, but can be expensive to produce. Interspecific hybridization, common among asexual epichloae, can pyramid the alkaloid biosynthesis genes. Compared to sexual epichloae, many asexual epichloae produce high levels of alkaloids – particularly lolines – suggesting that strict vertical transmission selects for enhanced capability of host protection. 相似文献