Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adding urine to a standard buffered fibrinogen solution and then coagulating it with thrombin gives reproducible coagulation times with normal urines. Coagulation of fibrinogen by thrombin is prolonged in acid solutions with a pH below six. Urines of high acidity lower the buffer pH of the fibrinogen solution below a value of six thus rendering the system uncoagulable or significantly prolonging the coagulation time. With this test system we found that out of 16 severe homograft rejections 15 were accompanied by a high acid excretion in six-hour urine specimens. Ten of these acid episodes became apparent 12 to 48 hr before clinical symptoms and before elevation of the serum creatinine could be detected.
 ...
PMID:A simple test for early detection of severe renal homograft rejection. 0 Jun 67

For comparative studies on the esterase activities of thrombin and trypsin N(alpha)-arylsulfonyl-L-arginine methyl esters were synthetised containing in aromatic ring substituents of different polar nature, size and hydrophobicity. The kinetics of their hydrolysis by thrombin and trypsin were measured. Values of Km and kcat in steady-state conditions were determined. It was shown, that thrombin-catalysed hydrolysis was more sensitive than that of trypsin to the nature of substituents of arylsulfonyl group and determined by their polar and steric effects. A line correlation between specificity constants (kcat/Km) and sigma and Es of substituents were demonstrated. The difference in reactivity of compounds under investigation is suggested to depend on alterations of stability of hydrogen bond between arylsulfonylamide nitrogen atom of substrate and the active center of the enzyme due to changes in the acidity of the arylsulfonylamide group affected by substituent of the benzene ring.
 ...
PMID:[Dependence of thrombin- and trypsin-catalyzed hydrolysis of N-alpha-arylsulfonyl-L-arginine methyl esters on the structure of acylamide part of substrates]. 2 Sep 97

In this study, aortic strips taken from mongrel dogs were used as experimental material. After preparation, the aortic strips were incubated in a designed control medium or an experimental medium (adding thrombin or epinephrine to the control medium). The pH value of each incubation medium mentioned above was adjusted with HCl or NaOH to a level of 8.0, 7.4, 7.0 and 6.6, respectively, in order to investigate the influence of medium acidity on the production of endothelin-1 from endothelial cells using aortic strips. After a designated time duration (one hour, three hours, six hours and 12 hours, respectively), the incubation media were collected for assay of endothelin-1. The results demonstrated that the endothelin-1 level of the incubation medium was elevated when: 1) the incubation time was lengthened; 2) the incubation medium was more acidic; 3) the aortic strips were incubated with a stimulant, such as thrombin and epinephrine; and 4) the endothelial cells on the aortic strips were intact. This indicates that the secretion of endothelin-1 is: 1) time-dependent, 2) pH-dependent, 3) stimulant-dependent and 4) endothelium-dependent.
 ...
PMID:Effect of pH on endothelin-1 secretion of aortic strips. 810 71

The growth factor-activated Na+/H+ exchanger is regulated by numerous stimuli, including polypeptide hormones, phorbol esters, cell acidity, and cell shrinkage. To determine whether this regulation occurs at a common site on the cytoplasmic domain of the Na+/H+ exchanger, we microinjected polyclonal antibodies (RP1-c28) to the C-terminal 157 amino acids of the molecule and measured cell pH changes after application of a variety of stimuli known to activate the Na+/H+ exchanger. Microinjection of approximately 10 fg of RP1-c28 antibody, but not control IgG, into single cultured fibroblasts blocked subsequent activation of the exchanger by both endothelin and alpha-thrombin. In contrast, microinjected RP1-c28 did not prevent activation of Na+/H+ exchange by phorbol esters, consistent with the observation that both endothelin-1 and alpha-thrombin retained the ability to activate exchange activity in protein kinase C-depleted cells. Finally, activation of Na+/H+ exchange by both cell acidity and osmotic shrinkage was also unaffected by microinjected RP1-c28 antibody. These data indicate that activation of Na+/H+ exchange by endothelin-1 and alpha-thrombin is mechanistically distinct both from activation by protein kinase C and activation by physical factors and probably occurs at a separate site on the exchanger molecule.
 ...
PMID:Role of cytoplasmic domain of the Na+/H+ exchanger in hormonal activation. 838 29

Heparin is a highly sulfated long-chain glycosaminoglycan utilized extensively for its anticoagulation properties, which has found widespread use as a general affinity ligand. The polysaccharide is composed of repeating units of uronic acid and glucosamine with great variability in sequence within the chain. The high degree of sulfation imparts strong acidity to the molecule and it may bond with many compounds simply by ionic interaction. In addition, it has been established that heparin contains certain specific monosaccharide sequences which act as unique binding sites for some proteins. For utilization as a biospecific affinity ligand it has been reported that heparin may optimally be immobilized by a single point of attachment through a terminal sugar residue. This method of immobilization allows unrestricted access to sequences within the polysaccharide chain required for biospecific interaction. Heparin immobilized to beaded agarose by single point attachment through its terminal formyl moiety was prepared. Chromatographic performance characteristics were evaluated using thrombin and antithrombin III as model compounds and elution profiles are presented. Additionally, stability of attachment was directly compared to several other commercially available supports. In conclusion, this end-point attached affinity matrix demonstrates high capacity and good stability compared with that of other methods of preparation.
 ...
PMID:End point attached heparin affinity matrix. 917 68

Anionic phospholipids are largely absent from the external leaflet of the plasma membrane of mammalian cells under normal conditions. Exposure of phosphatidylserine on the cell surface occurs during apoptosis, necrosis, cell injury, cell activation, and malignant transformation. In the present study, we determined whether anionic phospholipids become exposed on tumor vasculature. A monoclonal antibody, 9D2, which specifically recognizes anionic phospholipids, was injected into mice bearing a variety of orthotopic or ectopic tumors. Other mice received annexin V, a natural ligand that binds to anionic phospholipids. Both 9D2 and annexin V specifically localized to vascular endothelium in all of the tumors, and also to tumor cells in and around regions of necrosis. Between 15 and 40% of endothelial cells in tumor vessels were stained. No localization was detected on normal endothelium. Various factors and tumor-associated conditions known to be present in the tumor microenvironment were examined for their ability to cause exposure of anionic phospholipids in cultured endothelial cells, as judged by 9D2 and annexin V binding. Hypoxia/reoxygenation, acidity, thrombin, and inflammatory cytokines all induced exposure of anionic phospholipids. Hydrogen peroxide was also a strong inducer. Combined treatment with inflammatory cytokines and hypoxia/reoxygenation had greater than additive effects. Possibly, injury and activation of tumor endothelium by cytokines and reactive oxygen species induce exposure of anionic phospholipids, most likely phosphatidylserine. Anionic phospholipids on tumor vessels could potentially provide markers for tumor vessel targeting and imaging.
 ...
PMID:Increased exposure of anionic phospholipids on the surface of tumor blood vessels. 1241 38

Inorganic polyphosphate (polyP) has been identified and measured in human platelets. Millimolar levels (in terms of Pi residues) of short chain polyP were found. The presence of polyP of approximately 70-75 phosphate units was identified by 31P NMR and by urea-polyacrylamide gel electrophoresis of platelet extracts. An analysis of human platelet dense granules, purified using metrizamide gradient centrifugation, indicated that polyP was preferentially located in these organelles. This was confirmed by visualization of polyP in the dense granules using 4',6-diamidino-2-phenylindole and by its release together with pyrophosphate and serotonin upon thrombin stimulation of intact platelets. Dense granules were also shown to contain large amounts of calcium and potassium and both bafilomycin A1-sensitive ATPase and pyrophosphatase activities. In agreement with these results, when human platelets were loaded with the fluorescent calcium indicator Fura-2 acetoxymethyl ester to measure their intracellular Ca2+ concentration ([Ca2+]i), they were shown to possess a significant amount of Ca2+ stored in an acidic compartment. This was indicated by the following: 1) the increase in [Ca2+]i induced by nigericin, monensin, or the weak base, NH4Cl, in the nominal absence of extracellular Ca2 and 2) the effect of ionomycin, which could not take Ca2+ out of acidic organelles and was more effective after alkalinization of this compartment by the previous addition of nigericin, monensin, or NH4Cl. All of these characteristics of the platelet dense granules, together with their known acidity and high density (both by weight and by electron microscopy), are similar to those of acidocalcisomes (volutin granules, polyP bodies) of bacteria and unicellular eukaryotes. The results suggest that acidocalcisomes have been conserved during evolution from bacteria to humans.
 ...
PMID:Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. 1530 50

The studies on the human toxicity of nanoparticles (NPs) are far behind the rapid development of engineered functionalized NPs. Fullerene has been widely used as drug carrier skeleton due to its reported low risk. However, different from other kinds of NPs, fullerene-based NPs (C60 NPs) have been found to have an anticoagulation effect, although the potential target is still unknown. In the study, both experimental and computational methods were adopted to gain mechanistic insight into the modulation of thrombin activity by nine kinds of C60 NPs with diverse surface chemistry properties. In vitro enzyme activity assays showed that all tested surface-modified C60 NPs exhibited thrombin inhibition ability. Kinetic studies coupled with competitive testing using 3 known inhibitors indicated that six of the C60 NPs, of greater hydrophobicity and hydrogen bond (HB) donor acidity or acceptor basicity, acted as competitive inhibitors of thrombin by directly interacting with the active site of thrombin. A simple quantitative nanostructure-activity relationship model relating the surface substituent properties to the inhibition potential was then established for the six competitive inhibitors. Molecular docking analysis revealed that the intermolecular HB interactions were important for the specific binding of C60 NPs to the active site canyon, while the additional stability provided by the surface groups through van der Waals interaction also play a key role in the thrombin binding affinity of the NPs. Our results suggest that thrombin is a possible target of the surface-functionalized C60 NPs relevant to their anticoagulation effect.
 ...
PMID:Inhibition of thrombin by functionalized C60 nanoparticles revealed via in vitro assays and in silico studies. 2940 12

The past decades have witnessed the development of a field dedicated to targeting tumor vasculature for cancer therapy. In contrast to conventional chemotherapeutics that need to penetrate into tumor tissues for killing tumor cells, the agents targeting tumor vascular system have two major advantages: direct contact with vascular endothelial cells or the blood and less possibility to induce drug resistance because of high gene stability of endothelial cells. More specifically, various angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs) that block tumor blood supply to inhibit tumor progression, some of which have been applied clinically, have been described. However, off-target effects and high effective doses limit the utility of these formulations in cancer patients. Thus, new strategies with improved therapeutic efficacy and safety are needed for tumor vessel targeting therapy. With the burgeoning developments in nanotechnology, smart nanotherapeutics now offer unprecedented potential for targeting tumor vasculature. Based on specific structural and functional features of the tumor vasculature, a number of different nanoscale delivery systems have been proposed for cancer therapy. In this Account, we summarize several distinct strategies to modulate tumor vasculature with various smart nanotherapeutics for safe and effective tumor therapy developed by our research programs. Inspired by the blood coagulation cascade, we generated nanoparticle-mediated tumor vessel infarction strategies that selectively block tumor blood supply to starve the tumor to death. By specifically delivering thrombin loaded DNA nanorobots (Nanorobot-Th) into tumor vessels, an intratumoral thrombosis is triggered to induce vascular infarction and, ultimately, tumor necrosis. Mimicking the coagulation cascade, a smart polymeric nanogel achieves permanent and peripheral embolization of liver tumors. Considering the critical role of platelets in maintaining tumor vessel integrity, a hybrid (PLP-D-R) nanoparticle selectively depleting tumor-associated platelets (TAP) to boost tumor vessel permeability was developed for enhancing intratumoral drug accumulation. In addition, benefiting from a better understanding of the molecular and cellular underpinnings of vascular normalization, several tumor acidity responsive nanotherapeutics, encapsulating therapeutic peptides, and small interfering RNA were developed to correct the abnormal features of the tumor vasculature. This made the tumor vessels more efficient for drug delivery. While we are still exploring the mechanisms of action of these novel nanoformulations, we expect that the strategies summarized here will offer a promising platform to design effective next-generation nanotherapeutics against cancer and facilitate the clinical translation of smart nanotherapeutics that target tumor vasculature.
 ...
PMID:Smart Nanotherapeutic Targeting of Tumor Vasculature. 3143 71