Guanidine: A strong organic base existing primarily as guanidium ions at physiological pH. It is found in the urine as a normal product of protein metabolism. It is also used in laboratory research as a protein denaturant. (From Martindale, the Extra Pharmacopoeia, 30th ed and Merck Index, 12th ed) It is also used in the treatment of myasthenia and as a fluorescent probe in HPLC.Guanidines: A family of iminourea derivatives. The parent compound has been isolated from mushrooms, corn germ, rice hulls, mussels, earthworms, and turnip juice. Derivatives may have antiviral and antifungal properties.Protein Denaturation: Disruption of the non-covalent bonds and/or disulfide bonds responsible for maintaining the three-dimensional shape and activity of the native protein.Methylguanidine: A product of putrefaction. Poisonous.Circular Dichroism: A change from planar to elliptic polarization when an initially plane-polarized light wave traverses an optically active medium. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Protein Folding: Processes involved in the formation of TERTIARY PROTEIN STRUCTURE.Spectrometry, Fluorescence: Measurement of the intensity and quality of fluorescence.Urea: A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids.Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).Molecular Weight: The sum of the weight of all the atoms in a molecule.Kinetics: The rate dynamics in chemical or physical systems.Chromatography, Gel: Chromatography on non-ionic gels without regard to the mechanism of solute discrimination.Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins.Thermodynamics: A rigorously mathematical analysis of energy relationships (heat, work, temperature, and equilibrium). It describes systems whose states are determined by thermal parameters, such as temperature, in addition to mechanical and electromagnetic parameters. (From Hawley's Condensed Chemical Dictionary, 12th ed)Anilino Naphthalenesulfonates: A class of organic compounds which contain an anilino (phenylamino) group linked to a salt or ester of naphthalenesulfonic acid. They are frequently used as fluorescent dyes and sulfhydryl reagents.Hydrogen-Ion Concentration: The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH = log 1/2[1/(H+)], where (H+) is the hydrogen ion concentration in gram equivalents per liter of solution. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Electrophoresis, Polyacrylamide Gel: Electrophoresis in which a polyacrylamide gel is used as the diffusion medium.Enzyme Stability: The extent to which an enzyme retains its structural conformation or its activity when subjected to storage, isolation, and purification or various other physical or chemical manipulations, including proteolytic enzymes and heat.Poliovirus: A species of ENTEROVIRUS which is the causal agent of POLIOMYELITIS in humans. Three serotypes (strains) exist. Transmission is by the fecal-oral route, pharyngeal secretions, or mechanical vector (flies). Vaccines with both inactivated and live attenuated virus have proven effective in immunizing against the infection.Macromolecular Substances: Compounds and molecular complexes that consist of very large numbers of atoms and are generally over 500 kDa in size. In biological systems macromolecular substances usually can be visualized using ELECTRON MICROSCOPY and are distinguished from ORGANELLES by the lack of a membrane structure.Spectrophotometry, Ultraviolet: Determination of the spectra of ultraviolet absorption by specific molecules in gases or liquids, for example Cl2, SO2, NO2, CS2, ozone, mercury vapor, and various unsaturated compounds. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Temperature: The property of objects that determines the direction of heat flow when they are placed in direct thermal contact. The temperature is the energy of microscopic motions (vibrational and translational) of the particles of atoms.Protein Renaturation: The reconstitution of a protein's activity following denaturation.Receptors, sigma: A class of cell surface receptors recognized by its pharmacological profile. Sigma receptors were originally considered to be opioid receptors because they bind certain synthetic opioids. However they also interact with a variety of other psychoactive drugs, and their endogenous ligand is not known (although they can react to certain endogenous steroids). Sigma receptors are found in the immune, endocrine, and nervous systems, and in some peripheral tissues.Enzyme Reactivators: Compounds which restore enzymatic activity by removing an inhibitory group bound to the reactive site of the enzyme.Ultracentrifugation: Centrifugation with a centrifuge that develops centrifugal fields of more than 100,000 times gravity. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Sodium Dodecyl Sulfate: An anionic surfactant, usually a mixture of sodium alkyl sulfates, mainly the lauryl; lowers surface tension of aqueous solutions; used as fat emulsifier, wetting agent, detergent in cosmetics, pharmaceuticals and toothpastes; also as research tool in protein biochemistry.Hot Temperature: Presence of warmth or heat or a temperature notably higher than an accustomed norm.Cattle: Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.Ribonuclease, Pancreatic: An enzyme that catalyzes the endonucleolytic cleavage of pancreatic ribonucleic acids to 3'-phosphomono- and oligonucleotides ending in cytidylic or uridylic acids with 2',3'-cyclic phosphate intermediates. EC 3.1.27.5.Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.Disulfides: Chemical groups containing the covalent disulfide bonds -S-S-. The sulfur atoms can be bound to inorganic or organic moieties.Tryptophan: An essential amino acid that is necessary for normal growth in infants and for NITROGEN balance in adults. It is a precursor of INDOLE ALKALOIDS in plants. It is a precursor of SEROTONIN (hence its use as an antidepressant and sleep aid). It can be a precursor to NIACIN, albeit inefficiently, in mammals.Natal Teeth: Predeciduous teeth present at birth. They may be well formed and normal or may represent hornified epithelial structures without roots. They are found on the gingivae over the crest of the ridge and arise from accessory buds of the dental lamina ahead of the deciduous buds or from buds of the accessory dental lamina. (From Jablonski, Dictionary of Dentistry, 1992)Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Thiocyanates: Organic derivatives of thiocyanic acid which contain the general formula R-SCN.Escherichia coli: A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.Arginine Kinase: An enzyme that catalyzes the phosphorylation of the guanidine nitrogen of arginine in the presence of ATP and a divalent cation with formation of phosphorylarginine and ADP. EC 2.7.3.3.Proteoglycans: Glycoproteins which have a very high polysaccharide content.Echovirus 9: A species of ENTEROVIRUS associated with outbreaks of aseptic meningitis (MENINGITIS, ASEPTIC).Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Protein Structure, Secondary: The level of protein structure in which regular hydrogen-bond interactions within contiguous stretches of polypeptide chain give rise to alpha helices, beta strands (which align to form beta sheets) or other types of coils. This is the first folding level of protein conformation.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Drug Stability: The chemical and physical integrity of a pharmaceutical product.Dithionitrobenzoic Acid: A standard reagent for the determination of reactive sulfhydryl groups by absorbance measurements. It is used primarily for the determination of sulfhydryl and disulfide groups in proteins. The color produced is due to the formation of a thio anion, 3-carboxyl-4-nitrothiophenolate.Archaeoglobus: A genus of extremely thermophilic, sulfate-reducing archaea, in the family Archaeoglobaceae.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Protein Unfolding: Conformational transitions of the shape of a protein to various unfolded states.Adenosine Diphosphate Sugars: Esters formed between the aldehydic carbon of sugars and the terminal phosphate of adenosine diphosphate.Guanabenz: An alpha-2 selective adrenergic agonist used as an antihypertensive agent.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Dithioerythritol: A compound that, along with its isomer, Cleland's reagent (DITHIOTHREITOL), is used for the protection of sulfhydryl groups against oxidation to disulfides and for the reduction of disulfides to sulfhydryl groups.Histamine Agonists: Drugs that bind to and activate histamine receptors. Although they have been suggested for a variety of clinical applications histamine agonists have so far been more widely used in research than therapeutically.Pempidine: A nicotinic antagonist most commonly used as an experimental tool. It has been used as a ganglionic blocker in the treatment of hypertension but has largely been supplanted for that purpose by more specific drugs.Sulfhydryl Compounds: Compounds containing the -SH radical.Immunodiffusion: Technique involving the diffusion of antigen or antibody through a semisolid medium, usually agar or agarose gel, with the result being a precipitin reaction.Chemistry: A basic science concerned with the composition, structure, and properties of matter; and the reactions that occur between substances and the associated energy exchange.Bromides: Salts of hydrobromic acid, HBr, with the bromine atom in the 1- oxidation state. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)Chromatography, Ion Exchange: Separation technique in which the stationary phase consists of ion exchange resins. The resins contain loosely held small ions that easily exchange places with other small ions of like charge present in solutions washed over the resins.Chemical Phenomena: The composition, conformation, and properties of atoms and molecules, and their reaction and interaction processes.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Solubility: The ability of a substance to be dissolved, i.e. to form a solution with another substance. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)Phenformin: A biguanide hypoglycemic agent with actions and uses similar to those of METFORMIN. Although it is generally considered to be associated with an unacceptably high incidence of lactic acidosis, often fatal, it is still available in some countries. (From Martindale, The Extra Pharmacopoeia, 30th ed, p290)MercaptoethanolChromatography: Techniques used to separate mixtures of substances based on differences in the relative affinities of the substances for mobile and stationary phases. A mobile phase (fluid or gas) passes through a column containing a stationary phase of porous solid or liquid coated on a solid support. Usage is both analytical for small amounts and preparative for bulk amounts.Apoenzymes: The protein components of enzyme complexes (HOLOENZYMES). An apoenzyme is the holoenzyme minus any cofactors (ENZYME COFACTORS) or prosthetic groups required for the enzymatic function.Carbohydrates: The largest class of organic compounds, including STARCH; GLYCOGEN; CELLULOSE; POLYSACCHARIDES; and simple MONOSACCHARIDES. Carbohydrates are composed of carbon, hydrogen, and oxygen in a ratio of Cn(H2O)n.Trypsin: A serine endopeptidase that is formed from TRYPSINOGEN in the pancreas. It is converted into its active form by ENTEROPEPTIDASE in the small intestine. It catalyzes hydrolysis of the carboxyl group of either arginine or lysine. EC 3.4.21.4.Cimetidine: A histamine congener, it competitively inhibits HISTAMINE binding to HISTAMINE H2 RECEPTORS. Cimetidine has a range of pharmacological actions. It inhibits GASTRIC ACID secretion, as well as PEPSIN and GASTRIN output.Cyanamide: A cyanide compound which has been used as a fertilizer, defoliant and in many manufacturing processes. It often occurs as the calcium salt, sometimes also referred to as cyanamide. The citrated calcium salt is used in the treatment of alcoholism.Muramidase: A basic enzyme that is present in saliva, tears, egg white, and many animal fluids. It functions as an antibacterial agent. The enzyme catalyzes the hydrolysis of 1,4-beta-linkages between N-acetylmuramic acid and N-acetyl-D-glucosamine residues in peptidoglycan and between N-acetyl-D-glucosamine residues in chitodextrin. EC 3.2.1.17.Spectrophotometry: The art or process of comparing photometrically the relative intensities of the light in different parts of the spectrum.Guanethidine: An antihypertensive agent that acts by inhibiting selectively transmission in post-ganglionic adrenergic nerves. It is believed to act mainly by preventing the release of norepinephrine at nerve endings and causes depletion of norepinephrine in peripheral sympathetic nerve terminals as well as in tissues.

Subunit dissociation in fish hemoglobins. (1/2908)

The tetramer-dimer dissociation equilibria (K 4,2) of several fish hemoglobins have been examined by sedimentation velocity measurements with a scanner-computer system for the ultracentrifuge and by flash photolysis measurements using rapid kinetic methods. Samples studied in detail included hemoglobins from a marine teleost, Brevoortia tyrannus (common name, menhaden); a fresh water teleost, Cyprinus carpio, (common name, carp); and an elasmobranch Prionace glauca (common name, blue shark). For all three species in the CO form at pH 7, in 0.1 M phosphate buffer, sedimentation coefficients of 4.3 S (typical of tetrameric hemoglobin) are observed in the micromolar concentration range. In contrast, mammalian hemoglobins dissociate appreciably to dimers under these conditions. The inability to detect dissociation in three fish hemoglobins at the lowest concentrations examined indicates that K 4,2 must have a value of 10(-8) M or less. In flash photolysis experiments on very dilute solutions in long path length cells, two kinetic components were detected with their proportions varying as expected for an equilibrium between tetramers (the slower component) and dimers (the faster component); values of K 4,2 for the three fish hemoglobins in the range 10(-9) to 10(-8) M were calculated from these data. Thus, the values of K 4,2 for liganded forms of the fish hemoglobins appear to be midway between the value for liganded human hemoglobin (K 4,2 approximately 10(-6) M) and unliganded human hemoglobin (K 4,2 approximately 10(-12) M). This conclusion is supported by measurements on solutions containing guanidine hydrochloride to enhance the degree of dissociation. All three fish hemoglobins are appreciably dissociated at guanidine concentrations of about 0.8 M, which is roughly midway between the guanidine concentrations needed to cause comparable dissociation of liganded human hemoglobin (about 0.4 M) and unliganded human hemoglobin (about 1.6 M). Kinetic measurements on solutions containing guanidine hydrochloride indicated that there are changes in both the absolute rates and the proportions of the fast and slow components, which along with other factors complicated the analysis of the data in terms of dissociation constants. Measurements were also made in solutions containing urea to promote dissociation, but with this agent very high concentrations (about 6 M) were required to give measureable dissociation and the fish hemoglobins were unstable under these conditions, with appreciable loss of absorbance spectra in both the sedimentation and kinetic experiments.  (+info)

Effect of diabetes and aminoguanidine therapy on renal advanced glycation end-product binding. (2/2908)

BACKGROUND: Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic nephropathy, and aminoguanidine (AG) has been shown to decrease the accumulation of AGEs in the diabetic kidney. METHODS: This study investigates changes in AGE binding associated with diabetes in the rat kidney using in vitro and in vivo autoradiographic techniques. Male Sprague-Dawley rats were randomized into control and diabetic groups with and without AG treatment and were sacrificed after three weeks. Frozen kidney sections (20 microm) were incubated with [125I]-AGE-RNase or [125I]-AGE-BSA. To localize the AGE binding site, in vivo autoradiography was performed by injection of 15 microCi of [125I]-AGE-BSA into the abdominal aorta of the rat. RESULTS: Low-affinity binding sites specific for AGEs in the renal cortex (IC50 = 0.28 microm) were detected by in vitro autoradiography. There was a significant increase in [125I]-AGE binding in the diabetic kidney, which was prevented by AG treatment. Emulsion autoradiography revealed that binding was localized primarily to proximal tubules in the renal cortex. Renal AGE levels, as assessed by fluorescence or by radioimmunoassay, were increased after three weeks of diabetes. This increase was attenuated by AG therapy. CONCLUSIONS: AGE binding sites are present within the proximal tubules of the kidney and appear to be modulated by endogenous AGE levels. It remains to be determined if these binding sites represent receptors involved in clearance of AGEs or are linked to pathogenic pathways that lead to the development of diabetic nephropathy.  (+info)

Prevention of neointimal formation by a serine protease inhibitor, FUT-175, after carotid balloon injury in rats. (3/2908)

BACKGROUND AND PURPOSE: In vivo and vitro studies revealed the activation of thrombin and the complement system in vascular lesion formation during the process of atherosclerosis, along with pathological proliferation of smooth muscle cells. We examined the effect of the synthetic serine protease inhibitor FUT-175 (developed as a potent inhibitor of thrombin and the complement system) on vascular lesions using balloon dilatation-induced neointimal formation in the carotid artery of rats. METHODS: Sprague-Dawley (SD) rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. Three groups of these rats (n=8, each) were treated with daily intraperitoneal injections of 1 of the following doses of FUT-175: 0.5, 1.0, or 2.0 mg/d in 1 mL of saline for 7 consecutive days. The control group (n=8) was similarly treated with 1 mL of saline for 7 days. The injections were started immediately after balloon injury. Two weeks after the injury, the left carotid arteries were perfusion-fixed, and the areas of the neointimal and medial layer were analyzed under a microscope. RESULTS: A morphometric analysis revealed that there were significant differences in the intima-media ratio between the 4 groups treated with vehicle (saline) or a low, medium, or high dose of FUT-175 (1.45+/-0.11, 1.08+/-0.06, 0.71+/-0.04, or 0.32+/-0.04, respectively). This suppression was achieved in a dose-dependent manner by the administration of FUT-175 after balloon injury. In the histological study, it was demonstrated that FUT-175 suppresses the production of platelet-derived growth factor (PDGF)-BB in the neointima and the medial smooth muscle cell layer. CONCLUSIONS: After balloon injury activated proteases that were inhibited by FUT-175 were demonstrated to have an essential role in the development of the pathological thickening of the arterial wall.  (+info)

Adenosine inhibits the transfected Na+-H+ exchanger NHE3 in Xenopus laevis renal epithelial cells (A6/C1). (4/2908)

1. Adenosine influences the vectorial transport of Na+ and HCO3- across kidney epithelial cells. However, its action on effector proteins, such as the Na+-H+ exchanger NHE3, an epithelial brush border isoform of the Na+-H+ exchanger (NHE) gene family, is not yet defined. 2. The present study was conducted in Xenopus laevis distal nephron A6 epithelia which express both an apical adenosine receptor of the A1 type (coupled to protein kinase C (PKC)) and a basolateral receptor of the A2 type (coupled to protein kinase A (PKA)). The untransfected A6 cell line expresses a single NHE type (XNHE) which is restricted to the basolateral membrane and which is activated by PKA. 3. A6 cell lines were generated which express exogenous rat NHE3. Measurements of side-specific pHi recovery from acid loads in the presence of HOE694 (an inhibitor with differential potency towards individual NHE isoforms) detected an apical resistant Na+-H+ exchange only in transfected cell lines. The sensitivity of the basolateral NHE to HOE694 was unchanged, suggesting that exogenous NHE3 was restricted to the apical membrane. 4. Stimulation of the apical A1 receptor with N 6-cyclopentyladenosine (CPA) inhibited both apical NHE3 and basolateral XNHE. These effects were mimicked by the addition of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and partially prevented by the PKC inhibitor calphostin C which also blocked the effect of PMA. 5. Stimulation of the basolateral A2 receptor with CPA inhibited apical NHE3 and stimulated basolateral XNHE. These effects were mimicked by 8-bromo-cAMP and partially prevented by the PKA inhibitor H89 which entirely blocked the effect of 8-bromo-cAMP. 6. In conclusion, CPA inhibits rat NHE3 expressed apically in A6 epithelia via both the apical PKC-coupled A1 and the basolateral PKA-coupled A2 adenosine receptors.  (+info)

Modulation of human airway smooth muscle proliferation by type 3 phosphodiesterase inhibition. (5/2908)

Elevation in cell cAMP content can inhibit mitogenic signaling in cultured human airway smooth muscle (HASM) cells. We studied the effects of the type 3-selective phosphodiesterase inhibitor siguazodan, the type 4-selective phosphodiesterase inhibitor rolipram, and the nonselective inhibitor 3-isobutyl-1-methylxanthine (IBMX) on proliferation of cultured HASM cells. At concentrations selective for the type 3 phosphodiesterase isoform, siguazodan inhibited both [3H]thymidine incorporation (IC50 2 microM) and the increase in cell number (10 microM; 64% reduction) induced by platelet-derived growth factor-BB (20 ng/ml). These effects were mimicked by IBMX. At concentrations selective for type 4 phosphodiesterase inhibition, rolipram was without effect. A 20-min exposure to siguazodan and rolipram did not increase whole cell cAMP levels. However, in HASM cells transfected with a cAMP-responsive luciferase reporter (p6CRE/Luc), increases in cAMP-driven luciferase expression were seen with siguazodan (3.9-fold) and IBMX (16.5-fold). These data suggest that inhibition of the type 3 phosphodiesterase isoform present in airway smooth muscle results in inhibition of mitogenic signaling, possibly through an increase in cAMP-driven gene expression.  (+info)

Effects of prostaglandin F2 alpha on intracellular pH, intracellular calcium, cell shortening and L-type calcium currents in rat myocytes. (6/2908)

OBJECTIVE: We have studied the mechanisms underlying the positive inotropic action of prostaglandin F2 alpha (PGF2 alpha) by monitoring intracellular calcium transients, intracellular pH, L-type calcium currents and cell shortening in isolated ventricular myocytes. METHODS: Rat myocytes were loaded with fura-2AM for intracellular calcium measurements, or BCECF-AM for pH measurements. Cell shortening was recorded using an edge detection system, and L-type calcium currents measured using whole cell patch clamping. RESULTS: PGF2 alpha (3 nmol l-1-3 mumol l-1 increased single myocyte shortening and reduced resting cell length in a concentration-dependent manner. While myocyte shortening was increased by PGF2 alpha, this was not associated with any change in the amplitude of intracellular calcium transients, diastolic calcium, or L-type calcium currents. However, the same myocytes were capable of responding to catecholamines with increases in calcium transient amplitude and L-type calcium currents. PGF2 alpha (3 mumol l-1 caused a reversible rise in intracellular pH of 0.08 +/- 0.01 pH units (n = 5, p < 0.05). The Na(+)-H+ exchanger inhibitor, HOE 694 (10 mumol l-1, abolished the PGF2 alpha-induced rise in pH and the increase in cell shortening. PGF2 alpha-induced increases in cell shortening and intracellular pH were also attenuated by the protein kinase C (PKC) inhibitor, chelerythrine (2 mumol l-1. CONCLUSION: The positive inotropic action of PGF2 alpha appears to be mediated via activation of the Na(+)-H+ exchanger with the possible involvement of PKC. This suggests that PGF2 alpha-produces intracellular alkalosis, which then sensitizes cardiac myofilaments to calcium.  (+info)

Potentiation of anti-cancer drug activity at low intratumoral pH induced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) and its analogue benzylguanidine (BG). (7/2908)

Tumour-selective acidification is of potential interest for enhanced therapeutic gain of pH sensitive drugs. In this study, we investigated the feasibility of a tumour-selective reduction of the extracellular and intracellular pH and their effect on the tumour response of selected anti-cancer drugs. In an in vitro L1210 leukaemic cell model, we confirmed enhanced cytotoxicity of chlorambucil at low extracellular pH conditions. In contrast, the alkylating drugs melphalan and cisplatin, and bioreductive agents mitomycin C and its derivative EO9, required low intracellular pH conditions for enhanced activation. Furthermore, a strong and pH-independent synergism was observed between the pH-equilibrating drug nigericin and melphalan, of which the mechanism is unclear. In radiation-induced fibrosarcoma (RIF-1) tumour-bearing mice, the extracellular pH was reduced by the mitochondrial inhibitor m-iodobenzylguanidine (MIBG) or its analogue benzylguanidine (BG) plus glucose. To simultaneously reduce the intracellular pH, MIBG plus glucose were combined with the ionophore nigericin or the Na+/H+ exchanger inhibitor amiloride and the Na+-dependent HCO3-/Cl- exchanger inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). Biochemical studies confirmed an effective reduction of the extracellular pH to approximately 6.2, and anti-tumour responses to the interventions indicated a simultaneous reduction of the intracellular pH below 6.6 for at least 3 h. Combined reduction of extra- and intracellular tumour pH with melphalan increased the tumour regrowth time to 200% of the pretreatment volume from 5.7 +/- 0.6 days for melphalan alone to 8.1 +/- 0.7 days with pH manipulation (P < 0.05). Mitomycin C related tumour growth delay was enhanced by the combined interventions from 3.8 +/- 0.5 to 5.2 +/- 0.5 days (P < 0.05), but only in tumours of relatively large sizes. The interventions were non-toxic alone or in combination with the anti-cancer drugs and did not affect melphalan biodistribution. In conclusion, we have developed non-toxic interventions for sustained and selective reduction of extra- and intracellular tumour pH which potentiated the tumour responses to selected anti-cancer drugs.  (+info)

Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. (8/2908)

Neuroprotection against cerebral ischemia can be realized if the brain is preconditioned by previous exposure to a brief period of sublethal ischemia. The present study was undertaken to test the hypothesis that nitric oxide (NO) produced from the neuronal isoform of NO synthase (NOS) serves as a necessary signal for establishing an ischemia-tolerant state in brain. A newborn rat model of hypoxic preconditioning was used, wherein exposure to sublethal hypoxia (8% oxygen) for 3 hours renders postnatal day (PND) 6 animals completely resistant to a cerebral hypoxic-ischemic insult imposed 24 hours later. Postnatal day 6 animals were treated 0.5 hour before preconditioning hypoxia with the nonselective NOS inhibitor L-nitroarginine (2 mg/kg intraperitoneally). This treatment, which resulted in a 67 to 81% inhibition of calcium-dependent constitutive NOS activity 0.5 to 3.5 hours after its administration, completely blocked preconditioning-induced protection. However, administration of the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg intraperitoneally) before preconditioning hypoxia, which decreased constitutive brain NOS activity by 58 to 81%, was without effect on preconditioning-induced cerebroprotection, as was pretreatment with the inducible NOS inhibitor aminoguanidine (400 mg/kg intraperitoneally). The protective effects of preconditioning were also not blocked by treating animals with competitive [3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate; 5 mg/kg intraperitoneally] or noncompetitive (MK-801; 1 mg/kg intraperitoneally) N-methyl-D-aspartate receptor antagonists prior to preconditioning hypoxia. These findings indicate that NO production and activity are critical to the induction of ischemic tolerance in this model. However, the results argue against the involvement of the neuronal NOS isoform, activated secondary to a hypoxia-induced stimulation of N-methyl-D-aspartate receptors, and against the involvement of the inducible NOS isoform, but rather suggest that NO produced by the endothelial NOS isoform is required to mediate this profound protective effect.  (+info)

  • Development of guanidine catalysts is explored through direct iminium chloride and amine coupling, alongside a 2-chloro-l,3-dimethyl-IH-imidazol-:-3-ium chloride (DMC) induced thiourea cyclization. (brocku.ca)
  • We present a high-performance liquid chromatography (HPLC) and a capillary zone electrophoresis (CZE) method for the chiral separation of 3-phenyl-3-(2-pyridyl)propylamines, -guanidines and -guanidine-N-carboxylic acid esters. (uni-regensburg.de)
  • Polyhexamethylene guanidine (PHMG) is a guanidine derivative that is used as a biocidal disinfectant, often in the form of its salt polyhexamethylene guanidine phosphate (PHMG-P). Studies have shown that PHMG in solution has fungicidal as well as bactericidal activity against both Gram-positive and Gram-negative bacteria. (wikipedia.org)
  • Global Guanidine Phosphate (CAS 5423-23-4) Market New Project. (mynewsdesk.com)
  • This report provides a strategic analysis of the Guanidine Phosphate market and the growth estimates for the forecasted period.The market research analyst projects the global Guanidine Phosphate market to grow at a considerable CAGR, in terms of revenue,over the forecast period. (mynewsdesk.com)
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  • Additionally, the report also strategically analyzes the Guanidine Phosphate market with regards to individual growth trends, future prospects, and contribution of each segment to the market. (mynewsdesk.com)
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  • One aliquot (PBS aliquot) was diluted with 180 [micro]L of phosphate-buffered saline (PBS) and the other (G aliquot) was diluted with 180 [micro]L of 1M guanidine solution (G) (Sigma-Aldrich). (thefreedictionary.com)
  • Guanidine phosphate is often used as a flame retardant and antirust agent for wood fiber paper. (htfmarketreport.com)
  • The global Guanidine Dihydrogen Phosphate(CAS 5423-22-3) market was valued at xx million US$ in 2018 and will reach xx million US$ by the end of 2025, growing at a CAGR of xx% during 2019-2025. (htfmarketreport.com)
  • This report focuses on Guanidine Dihydrogen Phosphate(CAS 5423-22-3) volume and value at global level, regional level and company level. (htfmarketreport.com)
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  • Using the ligand, DMEGpy, three new copper guanidine-pyridine complexes could be synthesized and structurally characterized. (mdpi.com)
  • The anionic counterpart of guanidine, which is known as guanidinate, is also able to function as a ligand. (rsc.org)
  • Silia Bond ® Guanidine is a silica-supported diisopropylguanidine ligand. (silicycle.com)
  • A linear correlation between the enantiopurity of the catalyst and reaction product indicates the presence of a copper complex bearing a single guanidine ligand at the enantio-determining step. (ntu.edu.sg)
  • Their chemical structures and properties are also highly tunable as their flexibility and the number of guanidine groups can be tuned by altering the dendritic backbone or the linkages to the guanidine groups. (mdpi.com)
  • The potential of catalytic guanidine or guanidinate metal complexes to catalyse unique chemical transformations is immensely promising. (rsc.org)
  • Guanidine improves the action of a chemical in the body that regulates muscle cells. (drugster.info)
  • हम विशेष हैं Guanidine नाइट्रेट निर्माताओं और आपूर्तिकर्ताओं / कारखाने चीन से। कम कीमत / सस्ते के रूप में उच्च गुणवत्ता के साथ थोक Guanidine नाइट्रेट , चीन से अग्रणी ब्रांडों में से एक Guanidine नाइट्रेट में से एक, Beilite Chemical Co., Ltd. (dicyandiamideblt.com)
  • Borong White Guanidine Nitrat dengan kualiti tinggi sebagai harga rendah / murah, salah satu daripada White Guanidine Nitrat jenama terkemuka dari China, NINGXIA PURU CHEMICAL CO., LTD. (nxpuruchem.com)
  • Sprzedaż hurtowa Crystal Amino Guanidine Bicarbonate o wysokiej jakości w niskiej cenie / taniej, jednej z Crystal Amino Guanidine Bicarbonate wiodących marek z Chin, NINGXIA PURU CHEMICAL CO., LTD. (nxpuruchem.com)
  • Guanidines, which exist widely in nature, have been frequently utilised as strong Brønsted bases in organic chemistry. (rsc.org)
  • The guanidines were tested on the isolated spontaneously beating guinea-pig atrium for histamine H2-receptor affinity. (uni-regensburg.de)
  • Ion Exchange Chro/HPLC with 6M Guanidine or Some Detergent? (bio.net)
  • The biodegradation studies using UV-Vis spectrophotometry, HPLC, FTIR, and LC-MS indicated the production of the following metabolites: 2-chloro-5-methyl thiazole (CMT), methyl nitroguanidine (MNG), methyl 3-[thiazole-yl], and methyl guanidine (TMG). (hindawi.com)
  • HPLC-UV-ELSD-MS-guided fractionation of the anti-parasitic extract obtained from the marine sponge Monanchora arbuscula, collected off the southeastern coast of Brazil, led to the isolation of a series of guanidine and pyrimidine alkaloids. (fapesp.br)
  • The guanidine hybrid ligands, (tetramethylguanidine)methylenepyridine (TMGpy) and (dimethylethyleneguanidine)methylenepyridine (DMEGpy), were proven to be able to stabilize copper complexes active in the solvent-free polymerization of styrene at 110 °C using 1-phenylethylbromide as the initiator. (mdpi.com)
  • As ligands, guanidines can have different coordination modes with the metal center. (rsc.org)
  • Michael and his coworkers have synthesized, characterized, and studied the thermal degradation of a terpolymer prepared from salicylic acid, guanidine , and formaldehyde and 8-hydroxyquinoline-guanidineformaldehyde . (thefreedictionary.com)
  • The toxicities of these dendritic guanidines are also reported as well as their application towards the intracellular delivery of biologically significant cargos including proteins and nanoparticles. (mdpi.com)
  • It was interesting to study if the reactive blending via transamination reaction using terminal amine and guanidine groups of PHMG with ester units of PBAT at high temperature in an extruder leading to covalent immobilization was possible or not. (thefreedictionary.com)
  • Antitumor effects of EGFR antisense guanidine-based peptide nucleic ac" by Sufi M. Thomas, Bichismita Sahu et al. (cmu.edu)
  • Antitumor effects of EGFR antisense guanidine-based peptide nucleic acids in cancer models. (cmu.edu)
  • Herein, we report the development of cell-permeable, guanidine-based peptide nucleic acids targeting the epidermal growth factor receptor (EGFR) in preclinical models as therapeutic modality for head and neck squamous cell carcinoma (HNSCC) and nonsmall cell lung cancer (NSCLC). (cmu.edu)
  • A guanidine fragment enters into the composition of guanine (a component of nucleic acids), creatine, and arginine, the antibiotic streptomycin, and tetrodotoxin, a poison of animal origin. (thefreedictionary.com)