Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug resistance, accounting for therapeutic failure in the clinic, remains a major challenge to effectively manage cancer. Cyclosporin A (CsA) can reverse multidrug resistance (MDR), especially resistance to epidermal growth factor receptor tyrosine kinase inhibitors. However, the application of both drugs in cancer therapies is hampered by their poor aqueous solubility and low bioavailability due to oral administration. CsA augments the potency of gefitinib (Gef) in both Gef-sensitive and Gef-resistant cell lines. Here, we show that the simultaneous encapsulation of CsA and Gef within polyethylene glycol-block-poly(D, L-lactic acid) (PEG-PLA) produced a stable and systemically injectable nanomedicine, which exhibited a sub-50-nm diameter and spherical structures. Impressively, the co-delivery of therapeutics via single nanoparticles (NPs) outperformed the oral administration of the free drug combination at suppressing tumor growth. Furthermore, in vivo results indicated that CsA formulated in NPs sensitized Gef-resistant cells and Gef-resistant tumors to Gef treatment by inactivating the STAT3/Bcl-2 signaling pathway. Collectively, our nanomedicine approach not only provides an alternative administration route for the drugs of choice but also effectively reverses MDR, facilitating the development of effective therapeutic modalities for cancer.
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PMID:A nanomedicine approach enables co-delivery of cyclosporin A and gefitinib to potentiate the therapeutic efficacy in drug-resistant lung cancer. 2994 60

The aim of this study was to develop and validate the novel microLC/MS-MRM method for the simultaneous quantification of six proteins: angiopoietin 2 (Angpt-2), soluble form of fms-like tyrosine kinase 1 (sFLT-1), plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA), endocan (ESM-1), soluble form of E-selectin (sE-sel), and one peptide: adrenomedullin (ADM) in mouse plasma. Two approaches were compared: a stable isotope dilution (SID) method- used as a reference and a modified SID (mSID) procedure. In SID strategy the calibration curves were used, whereas in mSID the ratio between the chromatogram peak area of endogenous tryptic peptides at unknown concentration to chromatogram peak area of exogenous, stable isotope-labelled internal standards (SISs) added to the sample at known concentration was calculated. The microLC/MS-MRM method in the SID approach was linear from 0.250 pmol/mL to 250 pmol/mL for Angpt-2; 5 pmol/mL to 5000 pmol/mL for sFLT-1; 2.5 pmol/mL to 5000 pmol/mL for PAI-1; 0.375 pmol/mL to 250 pmol/mL for t-PA; 0.375 pmol/mL to 187.5 pmol/mL for ESM-1; 2.5 pmol/mL to 5000 pmol/mL for sE-sel and 0.375 pmol/mL to 250 pmol/mL for ADM. LPS-induced changes in plasma assessed based on SID and mSID approaches gave comparable quantitative results and featured LPS-induced dysregulation of endothelial permeability (Angpt-2, sFLT-1), glycocalyx injury (SDC-1) accompanied by a pro-thrombotic response (PAI-1). In addition, we applied microLC/MS-MRM method with mSID strategy to analyze human plasma samples from patients with chronic myeloid leukemia (CML) and obstructive sleep apnoea (OSA) and demonstrated usefulness of the method to characterize endothelial function in humans. In conclusion, the microLC/MS-MRM method with mSID strategy applied for simultaneous quantification of protein biomarkers of endothelial function in plasma represents a novel targeted proteomic platform for the comprehensive evaluation of endothelial function in mice and humans.
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PMID:Quantitative measurement of selected protein biomarkers of endothelial dysfunction in plasma by micro-liquid chromatography-tandem mass spectrometry based on stable isotope dilution method. 3060 7

The endothelium plays an important role in cancer metastasis, but the mechanisms involved are still not clear. In the present work, we characterised the changes in endothelial function at early and late stages of breast cancer progression in an orthotopic model of murine mammary carcinoma (4T1 cells). Endothelial function was analysed based on simultaneous microflow liquid chromatography-tandem mass spectrometry using multiple reaction monitoring (microLC/MS-MRM) quantification of 12 endothelium-related biomarkers, including those reflecting glycocalyx disruption - syndecan-1 (SDC-1), endocan (ESM-1); endothelial inflammation - vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin (E-sel); endothelial permeability - fms-like tyrosine kinase 1 (FLT-1), angiopoietin 2 (Angpt-2); and haemostasis - von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), as well as those that are pathophysiologically linked to endothelial function - adrenomedullin (ADM) and adiponectin (ADN). The early phase of metastasis in mouse plasma was associated with glycocalyx disruption (increased SDC-1 and ESM-1), endothelial inflammation [increased soluble VCAM-1 (sVCAM-1)] and increased vascular permeability (Angpt-2). During the late phase of metastasis, additional alterations in haemostasis (increased PAI-1 and vWF), as well as a rise in ADM and substantial fall in ADN concentration, were observed. In conclusion, in a murine model of breast cancer metastasis, we identified glycocalyx disruption, endothelial inflammation and increased endothelial permeability as important events in early metastasis, while the late phase of metastasis was additionally characterised by alterations in haemostasis.
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PMID:Early and late endothelial response in breast cancer metastasis in mice: simultaneous quantification of endothelial biomarkers using a mass spectrometry-based method. 3068 49

The overexpressed soluble fms-like tyrosine kinase 1 (sFLT-1) in placenta is considered to be a potential therapeutic target for preeclampsia (PE). How to achieve efficient intervention of sFLT1 expression in the placenta is an urgent problem to be solved. PEG-PLA nanoparticle generated by double-emulsion methods is a novel siRNA delivery system. Synthetic placental CSA binding peptide (P-CSA-BP) is effective for targeting lipid-polymer nanoparticle to the placenta. We conjugated P-CSA-BP to the surface of PEG-PLA nanoparticle to create a novel placenta specific sFLT1 siRNA delivery system for the therapy of PE. Nanoparticles were synthesized using double emulsion method and characterized by dynamic light scattering and transmission electron microscopy (TEM). RT-PCR was employed to evaluate mRNA level and protein level was analyzed by ELISA kit. The tissue distribution of nanoparticles was observed through ex vivo images. The concentrations of nanoparticles in organs were measured using high-performance liquid chromatography. T-NPsi sFLT1 had higher efficiency than NPsi sFLT1 in accumulating in HTR-8/SVneo cells and significantly decreased the expression of sFLT1. Intravenously administered T-NPsi sFLT1 specifically accumulated in placentas of mice. sFLT1 mRNA level in placenta and protein level in serum were declined by T-NPsi sFLT1 . T-NPsi sFLT1 shown no obvious toxic effect on both mother and fetus. The utility of T-NPsisFLT1 nanoparticles as a sFLT1 siRNA placenta specific delivery system significantly silenced sFLT1 in mice and is safe for both mother and fetus. This nanoparticle is a novel potential therapeutic strategy for PE.
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PMID:Trophoblast-Targeted Nanomedicine Modulates Placental sFLT1 for Preeclampsia Treatment. 3211 42


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