Gene/Protein Disease Symptom Drug Enzyme Compound
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Several estrogen-tethered platinum(IV) complexes were prepared and characterized by ESI-MS and (1)H NMR spectroscopy. Their design was inspired by the observation that estrogen receptor-positive cells exposed to the hormone are sensitized to cisplatin. Intracellular reduction of bis-estrogen-cis-diamminedichloroplatinum(IV), BEP(n) (where n = 1-5 methylene groups between Pt and estrogen), occurs to afford cisplatin and two equivalents of the linker-modified estrogen. The ability of BEP(n) to induce overexpression of HMGB1 was established by immunofluorescence microscopy. The cytotoxicity of the compounds was evaluated in ER(+) MCF-7 and ER(-) HCC-1937 human breast cancer cell lines. BEP3 selectively induces overexpression of HMGB1 in MCF-7 cells, compared to HCC-1937 cells, and enhances their sensitivity (IC(50) = 2.1 +/- 0.4 microM versus 3.7 +/- 0.9 microM, respectively) to the compound. The difference in compound activities and the potential of compounds of this class for treating breast and ovarian cancer are discussed.
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PMID:Synthesis, characterization, and cytotoxicity of a series of estrogen-tethered platinum(IV) complexes. 1512 50

N-linked glycosylation is prevalent in proteins destined for extracellular environments; nearly all secreted proteins are glycosylated. However, with respect to their glycosylation sites, little attention has been paid. Here, we report the analysis of N-glycosylation sites on secreted proteins of human hepatocellular carcinoma cells. For the enrichment of glycopeptides, capture methods with hydrophilic affinity (HA) and hydrazide chemistry (HC) were used complementarily. With the use of both methods in combination with nano-LC-ESI-MS/MS analysis, 300 different glycosylation sites within 194 unique glycoproteins were identified, and 172 glycosites have not been determined experimentally previously. A direct comparison between HA and HC methods was also investigated for the first time. In brief, in terms of selectivity for glycopeptides, HC is superior to HA (92.9% vs 51.3%); however, based on the number of glycosites identified, HA outweighs HC (265 vs 159). Furthermore, unavoidable contaminants such as actin and bovine serum albumin which are not N-glycosylated could be easily depleted by using this glycoproteomic strategy. As a consequence, more low-abundance and genuinely secreted proteins were identified. Among the glycoproteins identified, alpha-fetoprotein, CD44 and laminin have been reported to be implicated in HCC and its metastasis.
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PMID:Identification of N-glycosylation sites on secreted proteins of human hepatocellular carcinoma cells with a complementary proteomics approach. 1919 83

Metabolite profiling in biomarker discovery research requires new data preprocessing approaches to correlate specific metabolites to their biological origin. Mass spectrometry-based metabolomics often results in the observation of hundreds to thousands of features that are differentially regulated in biosamples. Extracting biomedical information from large metabolomic datasets by multivariate data analysis is of considerable complexity. Therefore, more efficient and optimized metabolomics data processing technologies are needed to improve MS applications in biomarker discovery. Here we use a sensitive ultra-performance LC-ESI/quadrupole-TOF high-definition mass spectrometry (UPLC-ESI-Q-TOF-MS) approach, in negative ion mode, to characterize metabolites. XCMS online analysis was used which incorporates novel nonlinear retention time alignment, matched filtration, peak detection, and peak matching. XCMS software can facilitate prioritization of the data and greatly increases the probability of identifying metabolites causally related to the phenotype of interest. 26 urinary differential metabolites contributing to the complete separation of HCC patients from matched healthy controls were identified involving the key metabolic pathways including tyrosine metabolism, glutathione metabolism, phenylalanine metabolism, ascorbate and aldarate metabolism, and arginine and proline metabolism. It demonstrates that high-throughput UPLC-ESI-Q-TOF-MS metabonomics combined with the proposed bioinformatic approach (based on XCMS) are pivotal to elucidate the developing biomarkers and physiological mechanism of disease in a clinical setting.
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PMID:High-throughput ultra-performance liquid chromatography-mass spectrometry characterization of metabolites guided by a bioinformatics program. 2382 Nov 29

Studying metal-protein interactions is key for understanding the fate of metallodrugs in biological systems. When a metal complex is not emissive and too weakly bound for mass spectrometry analysis, however, it may become challenging to study such interactions. In this work a synthetic procedure was developed for the alkyne functionalization of a photolabile ruthenium polypyridyl complex, [Ru(tpy)(bpy)(Hmte)](PF6)2, where tpy = 2,2':6',2''-terpyridine, bpy = 2,2'-bipyridine, and Hmte = 2-(methylthio)ethanol. In the functionalized complex [Ru(HCC-tpy)(bpy)(Hmte)](PF6)2, where HCC-tpy = 4'-ethynyl-2,2':6',2''-terpyridine, the alkyne group can be used for bioorthogonal ligation to an azide-labeled fluorophore using copper-catalyzed "click" chemistry. We developed a gel-based click chemistry method to study the interaction between this ruthenium complex and bovine serum albumin (BSA). Our results demonstrate that visualization of the interaction between the metal complex and the protein is possible, even when this interaction is too weak to be studied by conventional means such as UV-vis spectroscopy or ESI mass spectrometry. In addition, the weak metal complex-protein interaction is controlled by visible light irradiation, i.e., the complex and the protein do not interact in the dark, but they do interact via weak van der Waals interactions after light activation of the complex, which triggers photosubstitution of the Hmte ligand.
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PMID:Alkyne Functionalization of a Photoactivated Ruthenium Polypyridyl Complex for Click-Enabled Serum Albumin Interaction Studies. 3239 71