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41.
A proteomics approach to identifying key protein targets involved in VEGF inhibitor mediated attenuation of bleomycin‐induced pulmonary fibrosis 下载免费PDF全文
Yogesh M. Kulkarni Sucharita Dutta Anand Krishnan V. Iyer Rajkumar Venkatadri Vivek Kaushik Vani Ramesh Clayton A. Wright Oliver John Semmes Juan S. Yakisich Neelam Azad 《Proteomics》2016,16(1):33-46
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a life expectancy of less than 5 years post diagnosis for most patients. Poor molecular characterization of IPF has led to insufficient understanding of the pathogenesis of the disease, resulting in lack of effective therapies. In this study, we have integrated a label‐free LC‐MS based approach with systems biology to identify signaling pathways and regulatory nodes within protein interaction networks that govern phenotypic changes that may lead to IPF. Ingenuity Pathway Analysis of proteins modulated in response to bleomycin treatment identified PI3K/Akt and Wnt signaling as the most significant profibrotic pathways. Similar analysis of proteins modulated in response to vascular endothelial growth factor (VEGF) inhibitor (CBO‐P11) treatment identified natural killer cell signaling and PTEN signaling as the most significant antifibrotic pathways. Mechanistic/mammalian target of rapamycin (mTOR) and extracellular signal‐regulated kinase (ERK) were identified to be key mediators of pro‐ and antifibrotic response, where bleomycin (BLM) treatment resulted in increased expression and VEGF inhibitor treatment attenuated expression of mTOR and ERK. Using a BLM mouse model of pulmonary fibrosis and VEGF inhibitor CBO‐P11 as a therapeutic measure, we identified a comprehensive set of signaling pathways and proteins that contribute to the pathogenesis of pulmonary fibrosis that can be targeted for therapy against this fatal disease. 相似文献
42.
Ahmed Aljameeli Arvind Thakkar Shibu Thomas Vijaybasker Lakshmikanthan Kenneth A. Iczkowski Girish V. Shah 《PloS one》2016,11(3)
The role of neuroendocrine peptide calcitonin (CT) and its receptor (CTR) in epithelial cancer progression is an emerging concept with great clinical potential. Expression of CT and CTR is frequently elevated in prostate cancers (PCs) and activation of CT–CTR axis in non-invasive PC cells induces an invasive phenotype. Here we show by yeast-two hybrid screens that CTR associates with the tight junction protein Zonula Occludens-1 (ZO-1) via the interaction between the type 1 PDZ motif at the carboxy-terminus of CTR and the PDZ3 domain of ZO-1. Mutation of either the CTR C-PDZ-binding motif or the ZO-1-PDZ3 domain did not affect binding of CTR with its ligand or G-protein-mediated signaling but abrogated destabilizing actions of CT on tight junctions and formation of distant metastases by orthotopically implanted PC cells in nude mice, indicating that these PDZ domain interactions were pathologically relevant. Further, we observed CTR-ZO-1 interactions in PC specimens by proximity ligation immunohistochemistry, and identified that the number of interactions in metastatic PC specimens was several-fold larger than in non-metastatic PC. Our results for the first time demonstrate a mechanism by which PDZ-mediated interaction between CTR and ZO1 is required for CT-stimulated metastasis of prostate cancer. Since many receptors contain PDZ-binding motifs, this would suggest that PDZ-binding motif-adaptor protein interactions constitute a common mechanism for cancer metastasis. 相似文献
43.
Liza Bronner Murrison Ramya Ananthakrishnan Sumanya Sukumar Sheela Augustine Nalini Krishnan Madhukar Pai David W. Dowdy 《PloS one》2016,11(2)
Setting
Private practitioners are frequently the first point of healthcare contact for patients with tuberculosis (TB) in India. Inappropriate TB management practices among private practitioners may contribute to delayed TB diagnosis and generate drug resistance. However, these practices are not well understood. We evaluated diagnostic and treatment practices for active TB and benchmarked practices against International Standards for TB Care (ISTC) among private medical practitioners in Chennai.Design
A cross-sectional survey of 228 practitioners practicing in the private sector from January 2014 to February 2015 in Chennai city who saw at least one TB patient in the previous year. Practitioners were randomly selected from both the general community and a list of practitioners who referred patients to a public-private mix program for TB treatment in Chennai. Practitioners were interviewed using standardized questionnaires.Results
Among 228 private practitioners, a median of 12 (IQR 4–28) patients with TB were seen per year. Of 10 ISTC standards evaluated, the median of standards adhered to was 4.0 (IQR 3.0–6.0). Chest physicians reported greater median ISTC adherence than other MD and MS practitioners (score 7.0 vs. 4.0, P<0.001), or MBBS practitioners (score 7.0 vs. 4.0, P<0.001). Only 52% of all practitioners sent >5% of patients with cough for TB testing, 83% used smear microscopy for diagnosis, 33% monitored treatment response, and 22% notified TB cases to authorities. Of 228 practitioners, 68 reported referring all patients with new pulmonary TB for treatment, while 160 listed 27 different regimens; 78% (125/160) prescribed a regimen classified as consistent with ISTC. Appropriate treatment practices differed significantly between chest physicians and other MD and MS practitioners (54% vs. 87%, P<0.001).Conclusion
TB management practices in India’s urban private sector are heterogeneous and often suboptimal. Private providers must be better engaged to improve diagnostic capacity and decrease TB transmission in the community. 相似文献44.
Protein-glycan recognition is often mediated by multivalent binding. These multivalent bindings can be further complicated by cooperative interactions between glycans and individual glycan binding subunits. Here we have demonstrated a nanocube-based lipid bilayer array capable of quantitatively elucidating binding dissociation constants, maximum binding capacity, and binding cooperativity in a high-throughput format. Taking cholera toxin B subunit (CTB) as a model cooperativity system, we studied both GM1 and GM1-like gangliosides binding to CTB. We confirmed the previously observed CTB-GM1 positive cooperativity. Surprisingly, we demonstrated fucosyl-GM1 has approximately 7 times higher CTB binding capacity than GM1. In order to explain this phenomenon, we hypothesized that the reduced binding cooperativity of fucosyl-GM1 caused the increased binding capacity. This was unintuitive, as GM1 exhibited higher binding avidity (16 times lower dissociation constant). We confirmed the hypothesis using a theoretical stepwise binding model of CTB. Moreover, by taking a mixture of fucosyl-GM1 and GM2, we observed the mild binding avidity fucosyl-GM1 activated GM2 receptors enhancing the binding capacity of the lipid bilayer surface. This was unexpected as GM2 receptors have negligible binding avidity in pure GM2 bilayers. These unexpected discoveries demonstrate the importance of binding cooperativity in multivalent binding mechanisms. Thus, quantitative analysis of multivalent protein-glycan interactions in heterogeneous glycan systems is of critical importance. Our user-friendly, robust, and high-throughput nanocube-based lipid bilayer array offers an attractive method for dissecting these complex mechanisms. 相似文献
45.
46.
S. Siddalingappa Archana Sellappan Selvaraju B. Krishnan Binsila Arunachalam Arangasamy Stephen A. Krawetz 《Molecular reproduction and development》2019,86(11):1485-1504
Declining fertility rates in both human and animals is a cause for concern. While many of the infertility cases are due to known causes, idiopathic infertility is reported in 30% of the infertile couples. In such cases, 18% of the infertile males carry antisperm antibodies (ASAs). Such data are lacking in livestock, wherein 20–30% of the animals are being culled due to low fertility. In males, the blood–testis barrier (BTB) and biomolecules in the semen provide an immuno‐tolerant microenvironment for spermatozoa as they traverse the immunologic milieu of both the male and female reproductive tracts. For example, insults from environmental contaminants, infections and inflammatory conditions are likely to impact the immune privilege state of the testis and fertility. The female mucosal immune system can recognize allogenic spermatozoa‐specific proteins affecting sperm kinematics and sperm‐zona binding leading to immune infertility. Elucidating the functions and pathways of the immune regulatory molecules associated with fertilization are prerequisites for understanding their impact on fertility. An insight into biomolecules associated with spermatozoal immune tolerance may generate inputs to develop diagnostic tools and modulate fertility. High‐throughput sequencing technologies coupled with bioinformatics analyses provides a path forward to define the array of molecules influencing pregnancy outcome. This review discusses the seminal immune regulatory molecules from their origin in the testis until they traverse the uterine environment enabling fertilization and embryonic development. Well‐designed experiments and the identification of biomarkers may provide a pathway to understand the finer details of reproductive immunology that will afford personalized therapies. 相似文献
47.
48.
Density functional theory (DFT) calculations and molecular dynamics (MD) simulations on the atomic level were performed on
three different substituted banana-shaped compounds derived from 1,3-phenylene bis[4-(4-n-hexyloxyphenyliminomethyl)benzoate]
(P-6-O-PIMB). The DFT studies were carried out on the isolated molecules, and in the MD simulations clusters were treated
with up to 64 monomers. The effect of polar substituents, such as chlorine and the nitro group, on the central 1,3-phenylene
unit of banana-shaped compounds was investigated. In particular, flexibility, polarity, electrostatic potential (ESP) group
charge distributions, B-factors, bending angles and molecular lengths were considered. The MD results were analysed by trajectories
of significant torsion angles as well as order parameters such as radial atom pair distribution functions g(r), orientational
correlation functions g(o), diffusion coefficients (D) and root mean square deviations (RMSD) values. The g(r) and g(o) values
show that a certain long range order is generated by the introduction of a NO2 group in the 2-position of the central 1,3-phenylene ring. In contrast, the chlorination at the 4 and 6 positions of the
central 1,3-phenylene unit decreases the long range order tendency by its perturbation effect on the conformations in such
molecules. Moreover, g(r) and g(o) values, as well as diffusion coefficients, show that in the NO2 substituted compound the formation of microphase areas is preferred. Finally, the aggregation effect in such compounds was
studied in a systematic way by a comparison of the conformational properties of the isolated molecules and the monomers in
the clusters.
Figure Molecular dynamics (MD) simulations on the aggregation behaviour of substituted banana-shaped compounds
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
49.
Visceral leishmaniasis (VL) caused by Leishmania donovani is a major parasitic disease prevalent in endemic regions of Bihar in India. In the absence of good chemotherapeutic options, there is a need to develop an effective vaccine against VL which should be dependent on the generation of a T helper type 1 (Th1) immune response. We have shown that soluble proteins from promastigote of a new clinical isolate of L. donovani (2001) ranging from 68 to 97.4 kDa (F2 fraction), induce Th1 responses in the peripheral blood mononuclear cells of cured Leishmania patients and hamsters and also showed significant prophylactic potential. To understand the nature of F2 proteins, it was further characterized using 2-DE, MALDI-TOF and MALDI-TOF/TOF-MS. In all, 63 spots were cut from a CBB stained gel for analysis and data was retrieved for 52 spots. A total of 33 proteins were identified including six hypothetical/unknown proteins. Major immunostimulatory proteins were identified as elongation factor-2, p45, heat shock protein (HSP)70, HSP83, aldolase, enolase, triosephosphate isomerase, protein disulfideisomerase and calreticulin. This study substantiates the usefulness of proteomics in characterizing a complex protein fraction (F2) map of soluble L. donovani promastigote antigen identified as Th1 stimulatory for its potential as vaccine targets against VL. 相似文献
50.