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Effective Inhibitors (effective + inhibitor)
Selected AbstractsAnti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-,-D-arabinofuranosyl) cytosine (4,-thio-FAC) in human pancreatic and ovarian tumor xenograft modelsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2005Deborah A. Zajchowski Abstract 1-(2-Deoxy-2-fluoro-4-thio-,- D -arabinofuranosyl) cytosine (4,-thio-FAC) is a deoxycytidine analog that has been shown previously to have impressive anti-proliferative and cytotoxic effects in vitro and in vivo toward colorectal and gastric tumors. In our present studies, the pharmacokinetic behavior in nude mice and the effectiveness of 4,-thio-FAC against human pancreatic and ovarian tumor growth were assessed in comparison with standard chemotherapeutic agents. Potent in vitro anti-proliferative effects were observed against pancreatic (Capan-1, MIA-PaCa-2, BxPC-3) and ovarian (SK-OV-3, OVCAR-3, ES-2) cancer cell lines with IC50 of 0.01,0.2 ,M. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously (s.c.) implanted human pancreatic tumor xenografts or intraperitoneally (i.p.) disseminated human ovarian xenografted tumors. Oral daily administration of 4,-thio-FAC for 8,10 days significantly inhibited the growth of gemcitabine-resistant BxPC-3 pancreatic tumors and induced regression of gemcitabine-refractory Capan-1 tumors. 4,-Thio-FAC was also a highly effective inhibitor of ovarian peritoneal carcinomatosis. In the SK-OV-3 and ES-2 ovarian cancer models, 4,-thio-FAC prolonged survival to a greater extent than that observed with gemcitabine. Furthermore, the superiority of 4,-thio-FAC to carboplatin and paclitaxel was demonstrated in the ES-2 clear cell ovarian carcinoma model. Studies provide evidence that 4,-thio-FAC is a promising new alternative to gemcitabine and other chemotherapeutic drugs in the treatment of a variety of tumor indications, including pancreatic and ovarian carcinoma. © 2004 Wiley-Liss, Inc. [source] Delivery of endostatin in experimental cancer therapyINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 6 2002Dag R. Sorensen Summary. Endostatin, the 20 kDa C-terminal fragment of collagen XVIII, has been shown to be an effective inhibitor of tumour angiogenesis and growth in different experimental systems and is currently in Phase II/III clinical trials. One challenging aspect of anti-angiogenic treatment is the mode of delivery of the active compound. In this paper we review some of the basic knowledge of endostatin and look specifically into the different possible ways in which endostatin may be administered. [source] Antiallergic Activities of Pigmented Rice Bran Extracts in Cell AssaysJOURNAL OF FOOD SCIENCE, Issue 9 2007Sun Phil Choi ABSTRACT:, Using a panel of chemical, biochemical, and cell assays, we determined inhibitory effects of extracts of the pigmented black rice brans on in vitro allergic reactions. Ethanol-water (70% v/v) extracts from 5 pigmented brans were found to be more effective than an extract from a nonpigmented rice cultivar in suppressing the release of histamine and ,-hexosaminidase from basophilic RBL-2H3 cells stimulated with both Ionophore A23187 and immunoglobulin E (IgE)-antigen complexes. Suppression was also obtained with A23187-stimulated rat peritoneal mast cells. The extent of inhibition of these 2 markers of the immune response was accompanied by an influx of calcium ions. The inhibition of the immune process by the pigmented brans was confirmed by the observed modulation of the proinflammatory cytokine gene expressions and cytokine release, as indicated by the reduction in tumor necrosis factor (TNF)-,, interleukin (IL)-1,, IL-4, and IL-6 mRNA expressions determined with the reverse transcription-polymerase chain reaction (RT-PCR). Reduction of TNF-,, IL-1,, and IL-6 protein release from both the cultured cell line and peritoneal cells was further confirmed by enzyme-linked immunoadsorbent assays. Rice bran from the LK1-3-6-12-1-1 cultivar was the most effective inhibitor in all assays. This particular rice variety merits further evaluation as part of a human diet to ascertain its potential to protect against allergic diseases such as hay fever and asthma. [source] Polyphenol Oxidase from Bean Sprouts (Glycine max L.)JOURNAL OF FOOD SCIENCE, Issue 1 2003T. Nagai ABSTRACT: Polyphenol oxidase (PPO) was purified and characterized from bean sprouts by ammonium sulfate precipitation, DEAE-Toyopearl 650M, CM-Toyopearl 650M, SuperQ-Toyopearl 650S and QAE-Toyopearl 550C column chromatographies. Substrate staining of the crude extract on electrophoresis showed the presence of 2 isozymic forms of this enzyme. The molecular weight of the purified enzyme was estimated to be about 54 kDa. The optimum pH was 9.0 and optimum temperature 40 °C. Heat inactivation occurred about 30 °C. PPO showed activity to catechol, pyrogallol and dopamine. These compounds such as ascorbic acid, L-cysteine, 2-mercaptoethanol, and glutathione used was the effective inhibitor. Enzyme activity was maintained for 7 d at 4 °C but suddenly decreased after 8 d. [source] Inhibition of Porphyromonas gingivalis proteinases (gingipains) by chlorhexidine: synergistic effect of Zn(II)MOLECULAR ORAL MICROBIOLOGY, Issue 4 2006C. A. Cronan Background/aims:, Gingipains, proteolytic enzymes produced by the periodontal pathogen Porphyromonas gingivalis, are regarded as virulence factors in the pathogenesis of periodontitis. Inhibition of gingipain activity therefore may have therapeutic potential, and it has been suggested that chlorhexidine may inhibit the activities of these enzymes. The purposes of the present study were to examine systematically the inhibitory effects of chlorhexidine on three purified gingipains and to determine the effect of Zn(II) on chlorhexidine inhibition. Methods:, The activities of lys-gingipain (Kgp) and two forms of arg-gingipain (RgpB and HRgpA) were measured in the presence of varying concentrations of chlorhexidine and with chlorhexidine supplemented with Zn(II). Inhibition constants (Ki's) were determined for chlorhexidine alone and in the presence of Zn(II). Fractional inhibitory constant indices were calculated to assess the synergy of the chlorhexidine,Zn(II) inhibition. Results:, RgpB, HRgpA, and Kgp were all inhibited by chlorhexidine with Ki's in the micromolar range. For RgpB and HRgpA, the inhibitory effects of chlorhexidine were enhanced 3,30-fold by Zn(II). The chlorhexidine,Zn(II) interaction was synergistic for inhibition of HRgpA and RgpB. For Kgp, the effect of Zn(II) on chlorhexidine inhibition was antagonistic. Conclusions:, Chlorhexidine is an effective inhibitor of gingipains, and the inhibition of R-gingipains is enhanced by Zn(II). A mixture of chlorhexidine and Zn(II) may be useful as an adjunct in the treatment of periodontitis and in the post-treatment maintenance of periodontitis patients. [source] The high-resolution structure of dihydrodipicolinate synthase from Escherichia coli bound to its first substrate, pyruvateACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 12 2008Sean R. A. Devenish Dihydrodipicolinate synthase (DHDPS) mediates the key first reaction common to the biosynthesis of (S)-lysine and meso -diaminopimelate, molecules which play a crucial cross-linking role in bacterial cell walls. An effective inhibitor of DHDPS would represent a useful antibacterial agent; despite extensive effort, a suitable inhibitor has yet to be found. In an attempt to examine the specificity of the active site of DHDPS, the enzyme was cocrystallized with the substrate analogue oxaloacetate. The resulting crystals diffracted to 2.0,Å resolution, but solution of the protein structure revealed that pyruvate was bound in the active site rather than oxaloacetic acid. Kinetic analysis confirmed that the decarboxylation of oxaloacetate was not catalysed by DHDPS and was instead a slow spontaneous chemical process. [source] Inhibition of Amyloid Fibrillization of Hen Egg-White Lysozymes by Rifampicin and p -BenzoquinoneBIOTECHNOLOGY PROGRESS, Issue 3 2007Valerie H. Lieu It has been reported that more than 20 different human proteins can fold abnormally, resulting in the formation of pathological deposits and several lethal degenerative diseases. Despite extensive investigations on amyloid fibril formation, the detailed molecular mechanism remained rather elusive. The current research, utilizing hen egg-white lysozymes as a model system, is aimed at exploring inhibitory activities of two potential molecules against lysozyme fibril formation. We first demonstrated that the formation of lysozyme amyloid fibrils at pH 2.0 was markedly enhanced by the presence of agitation in comparison with its quiescent counterpart. Next, via numerous spectroscopic techniques and transmission electron microscopy, our results revealed that the inhibition of lysozyme amyloid formation by either rifampicin or its analogue p -benzoquinone followed a concentration-dependent fashion. Furthermore, while both inhibitors were shown to acquire an anti-aggregating and a disaggregating activity, rifampicin, in comparison with p -benzoquinone, served as a more effective inhibitor against in vitro amyloid fibrillogenesis of lysozyme. It is our belief that the data reported in this work will not only reinforce the findings validated by others that rifampicin and p -benzoquinone serve as two promising preventive molecules against amyloid fibrillogenesis, but also shed light on a rational design of effective therapeutics for amyloidogenic diseases. [source] The long-acting ,-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009Anne-Marie Scola Background and purpose:, The long-acting ,2 -adrenoceptor agonist, indacaterol, has been developed as a bronchodilator for the therapeutic management of respiratory diseases. The aim of the present study was to determine whether indacaterol has any anti-inflammatory activity. To this end, the effects of indacaterol on human lung mast cell responses were investigated. Experimental approach:, The effects of indacaterol, and the alternative long-acting ,-agonists formoterol and salmeterol, were investigated on the IgE-dependent release and generation of histamine, cysteinyl-leukotrienes and prostaglandin D2 from human lung mast cells. Moreover, the extent to which long-term (24,72 h) incubation of mast cells with long-acting ,-agonists impaired the subsequent ability of ,-agonists to inhibit mast cell responses was assessed. Key results:, Indacaterol was as potent and as efficacious as the full agonist, isoprenaline (EC50, ,4 nmol·L,1), at inhibiting the IgE-dependent release of histamine from mast cells. Formoterol was a full agonist whereas salmeterol was a partial agonist as inhibitors of histamine release. All three long-acting ,-agonists were effective inhibitors of the IgE-dependent generation of cysteinyl-leukotrienes and prostaglandin D2. Long-term incubation of mast cells with long-acting ,-agonists led to a reduction in the subsequent ability of ,-agonists to stabilize mast cell responses. This tendency to induce functional desensitization was least evident for indacaterol. Conclusions and implications:, Indacaterol is an effective inhibitor of the release of mediators from human lung mast cells. This suggests that, as well as bronchodilation, mast cell stabilization may constitute an additional therapeutic benefit of indacaterol. [source] Synthesis, SAR, and Biological Evaluation of ,-Sulfonylphosphonic Acids as Selective Matrix Metalloproteinase InhibitorsCHEMMEDCHEM, Issue 3 2009Maria Teresa Rubino Dr. Abstract Selective MMP inhibitors: Eleven ,-sulfonylphosphonates were synthesized and tested as MMP inhibitors. The IC50 values for most of them are in the nanomolar range against MMP-2, -8, -13, and -14, with an interesting selectivity profile versus MMP-9. Eleven simple , -sulfonylphosphonates, new analogues of previously reported , -sulfonylaminophosphonates, were prepared and tested as MMP inhibitors. The IC50 values of most of these compounds are in the nanomolar range against MMP-2, -8, -13, and -14. Compound 11 proved to be the most effective inhibitor of MMP-2 (IC50=60,nM), with interesting selectivity versus the antitarget enzymes MMP-3 and MMP-9. The mode of binding of the new phosphonates in the active site of MMP-2 was studied, and variations in inhibition was explained by means of molecular modeling. [source] CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivityEXPERIMENTAL DERMATOLOGY, Issue 4 2005Edward E. S. Nieuwenhuis Abstract:, CD1d-restricted T-cells are activated by glycolipids presented by the major histocompatibility complex class-Ib molecule CD1d, found on the surface of antigen-presenting cells (APC). This interaction between APC, most notably dendritic cells (DC), and CD1d-restricted T-cells is an important regulatory step in the initiation of adaptive immune responses. It is well known that DC play a crucial role in the induction of contact hypersensitivity (CHS), a frequently studied form of in vivo T-cell-mediated immunity. In this study, we show that CD1d-restricted T-cells are also necessary for CHS, because both wild-type mice treated systemically or topically with CD1d glycolipid antagonists and CD1d-restricted T-cell-null mice have markedly diminished CHS responses. Thus, pharmacologic antagonists of CD1d can be used as effective inhibitors of CHS, a prototype for a variety of delayed-type tissue hypersensitivity responses. [source] Some properties of polyphenol oxidase from lilyINTERNATIONAL JOURNAL OF FOOD SCIENCE & TECHNOLOGY, Issue 1 2008Ying Yang Summary A study of crude polyphenol oxidase (PPO) from lily bulbs was carried out to provide information useful for guiding food processing operations. Optimum pH for the enzyme activity in the presence of catechol, were 4.0 and 7.0 at room temperature(approximately 20 °C) and the enzyme was stable in the pH range from 5.0 to 6.5 at 4 °C for 10 h. Its optimum temperature was 40 °C and the heat inactivation of the enzyme followed first-order kinetics. Lily PPO possessed a diphenolase activity toward catechol, catechin and gallic acid; catechin was the best substrate for the enzyme considering the Vmax/Km ratio. The most effective enzyme inhibitor was sodium sulphite, although ascorbic acid, l -cysteine and thiourea were also effective inhibitors at high concentration. But NaCl and citric acid were poor inhibitors of the enzyme. Data generated by this study might help to better prevent lily bulbs browning. [source] A structure/function study of polyaminoamide dendrimers as silica scale growth inhibitorsJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 6 2005Konstantinos D Demadis Abstract Dendrimers have attracted immense attention during the last decade due to their interesting properties both from a basic and an applied research viewpoint. Encapsulation of metal nanoparticles for catalysis, drug delivery and light harvesting are only some applications of dendrimers that are breaking new ground. A novel application of dendrimer technology is described in the present paper that relates to industrial water treatment. Industrial water systems often suffer from undesirable inorganic deposits. These can form either in the bulk or on metallic surfaces, such as heat exchangers or pipelines. Silica (SiO2) scale formation and deposition is a major problem in high-silica-containing cooling waters. Scale prevention rather than removal is highly desired. In this paper, benchtop screening tests on various silica inhibition chemistries are reported, with emphasis on materials with a dendrimeric structure. Specifically, the inhibition properties of commercially available STARBURST® polyaminoamide (PAMAM) dendrimers generations 0.5, 1, 1.5, 2, and 2.5 are investigated in detail together with other commonly-used scale inhibitors. Experimental results show that inhibition efficiency largely depends on structural features of PAMAM dendrimers such as generation number and nature of the end groups. PAMAM dendrimers are effective inhibitors of silica scale growth at 40 ppm dosage levels. PAMAM dendrimers also act as silica nucleators, forming SiO2,PAMAM composites. This occurs because the SiO2 formed by incomplete inhibition interacts with cationic PAMAM-1 and -2. The general scope of silica formation and inhibition in industrial waters is also discussed. Copyright © 2005 Society of Chemical Industry [source] CHARACTERIZATION OF POLYPHENOL OXIDASE FROM ROOSTER POTATO (SOLANUM TUBEROSUM CV ROOSTER)JOURNAL OF FOOD BIOCHEMISTRY, Issue 1 2010D. NI EIDHIN ABSTRACT The isolation and purification of polyphenol oxidase from potatoes (Solanum tuberosum cv. Rooster) is described. A 64-fold purified preparation has been obtained with 10% yield by a procedure involving (NH4)2SO4 precipitation, phenyl sepharose chromatography, ion exchange chromatography and hydroxyapatite chromatography. The partially purified enzyme has both cresolase and catecholase activity. Activity was lower toward monophenols than diphenols. Enzyme activity was optimal at pH 6.0,6.5 and at 30C. Greater than 50% activity was retained during storage for 72 h at pH 6.0,7.5. Residual activity was greater than 50% after incubation at 20C for 72 h, 30C for 48 h, 40C for 24 h, 50C for 2 h and 60C for 15 min. The most effective inhibitors tested were sodium metabisulfite and ascorbic acid. Sodium dodecyl sulphate appeared to activate the enzyme. The enzyme was capable of cross-linking casein but did not increase gel-strengths in acidified milk gels. PRACTICAL APPLICATIONS Rooster is the most important potato cultivar grown in Ireland and data on its isolation and characterization has not been reported previously. This work describes a method to isolate polyphenol oxidase and characterization of the enzyme. Information on characterization of the enzyme could be valuable in relation to control of enzymatic browning during current processing and in minimum processing. There is potential for use of the enzyme in the emerging cross-linking area, as the results show some success and there may be potential of more cross-linking as the field develops and as interest in natural methods of cross-linking for food texture grows. This could lead to an important use for potato waste. Food product applications are given. [source] Polyphenol Oxidase from Apple (Malus domestica Borkh. cv Bramley's Seedling): Purification Strategies and CharacterizationJOURNAL OF FOOD SCIENCE, Issue 1 2006Deirdre M. Ni Eidhin ABSTRACT Polyphenol oxidase (PPO) was isolated from Bramley's Seedling apples with 75.7-fold purification and 26.5% recovery by ammonium sulfate precipitation, phenyl sepharose chromatography, ion exchange chromatography, and hydroxyapatite chromatography. Molecular weight was estimated to be about 45 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE). Optimum PPO activity was at pH 6.5 and greater than 50% activity was retained during storage for 72 h at pH 5.5 to 6.5. Optimum temperature for activity was 30 °C and the enzyme had residual activity of greater than 50% during storage for 72 h at 20 °C to 30 °C and for 24 h at 40 °C to 50 °C. Of the substrates tested, activity was greatest with 4-methylcatechol followed by catechol, pyrogallol, and (,)epicatechin. The most effective inhibitors tested were sodium metabisulfite and ascorbic acid. [source] Thermodynamic micellization model for asphaltene precipitation inhibitionAICHE JOURNAL, Issue 2 2000Huanquan Pan Aromatic solvents and oil-soluble amphiphiles are recognized as asphaltene precipitation inhibitors in oil production and transportation. In the absence of the model describing the effect of these inhibitors on asphaltene precipitation from crudes, proposed is a thermodynamic micellization model explaining the inhibition mechanism for both aromatic solvents and oil-soluble amphiphiles. The model shows that aromatic solvents are concentrated in the micellar shell, and the interfacial tension between the asphaltene micellar core and shell is reduced as the micelles becomes stabler. A crude, mixed with a small amount of an oil-soluble amphiphile, achieves a high micellar stability. The amphiphiles behave like resin species of the crude and coadsorb onto the micellar core with resins. The adsorption enthalpy of an amphiphile onto the micellar core is much higher than that of the resin and, therefore, amphiphiles can be very effective inhibitors. The results suggest that the adsorption enthalpy data can be used to screen the amphiphiles for asphaltene precipitation inhibition. For a given oil-soluble amphiphile, this model can predict the amount of the amphiphile required to inhibit the precipitation. [source] Therapeutic applications of glycosidic carbonic anhydrase inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 3 2009Jean-Yves Winum Abstract The zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1) are very efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate and hence play an important physiological role. In humans, 16 different isozymes have been described, some of them being involved in various pathological disorders. Several of these isozymes are considered as drug targets, and the design of selective inhibitors is a long-standing goal that has captured the attention of researchers for 40 years and has lead to clinical applications against different pathologies such as glaucoma, epilepsy, and cancer. Among the different strategies developed for designing selective CA inhibitors (CAIs), the "sugar approach" has recently emerged as a new attractive and versatile tool. Incorporation of glycosyl moieties in different aromatic/heterocyclic sulfonamide/sulfamides/sulfamates scaffolds has led to the development of numerous and very effective inhibitors of potential clinical value. The clinical use of a highly active carbohydrate-based CA inhibitor, i.e., topiramate, constitutes an interesting demonstration of the validity of this approach. Other carbohydrate-based compounds also demonstrate promising potential for the treatment of ophthalmologic diseases. This review will focus on the development of this emerging sugar-based approach for the development of CAIs. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 3, 419-435, 2009 [source] Bis(1H -indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitroBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2009Florian Heidel Summary Inhibition of the mutated fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is a promising therapeutic strategy in acute myeloid leukaemia (AML). However, development of resistance to FLT3 tyrosine kinase inhibitors (TKI), such as PKC412A, has been described recently. This observation may have an increasing impact on the duration of response and relapse rates in upcoming clinical trials employing FLT3-TKI. Herein we investigated two representatives of a novel class of FLT3-TKI: Bis(1H -indol-2-yl)methanones. Both compounds effectively induced apoptosis in FLT3-internal tandem duplicate (ITD)-transfected murine myeloid cells and in primary FLT3-ITD positive blasts. Combination of both compounds with chemotherapy revealed synergistic effects in apoptosis assays. The compounds did not show significant toxicity in human bone marrow cells derived from healthy donors. Compound102 overcame resistance to PKC412 within a non-myelotoxic dose-range. Western Blotting experiments of 32D-FLT3-ITD cells showed dose-dependent dephosphorylation of FLT3-ITD and of its downstream targets STAT5, AKT and ERK upon incubation with either compound. In conclusion, bis(1H -indol-2-yl)methanones overcome resistance mediated by FLT3-ITD mutations at position N676 and show strong efficacy in FLT3-ITD-positive cells alone as well as in combination with chemotherapy. We propose that further development of methanone compounds overcoming resistance to currently established FLT3-TKIs is an important step forward to an anticipated need within our future therapeutic algorithm in FLT3-ITD-positive AML. [source] The long-acting ,-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009Anne-Marie Scola Background and purpose:, The long-acting ,2 -adrenoceptor agonist, indacaterol, has been developed as a bronchodilator for the therapeutic management of respiratory diseases. The aim of the present study was to determine whether indacaterol has any anti-inflammatory activity. To this end, the effects of indacaterol on human lung mast cell responses were investigated. Experimental approach:, The effects of indacaterol, and the alternative long-acting ,-agonists formoterol and salmeterol, were investigated on the IgE-dependent release and generation of histamine, cysteinyl-leukotrienes and prostaglandin D2 from human lung mast cells. Moreover, the extent to which long-term (24,72 h) incubation of mast cells with long-acting ,-agonists impaired the subsequent ability of ,-agonists to inhibit mast cell responses was assessed. Key results:, Indacaterol was as potent and as efficacious as the full agonist, isoprenaline (EC50, ,4 nmol·L,1), at inhibiting the IgE-dependent release of histamine from mast cells. Formoterol was a full agonist whereas salmeterol was a partial agonist as inhibitors of histamine release. All three long-acting ,-agonists were effective inhibitors of the IgE-dependent generation of cysteinyl-leukotrienes and prostaglandin D2. Long-term incubation of mast cells with long-acting ,-agonists led to a reduction in the subsequent ability of ,-agonists to stabilize mast cell responses. This tendency to induce functional desensitization was least evident for indacaterol. Conclusions and implications:, Indacaterol is an effective inhibitor of the release of mediators from human lung mast cells. This suggests that, as well as bronchodilation, mast cell stabilization may constitute an additional therapeutic benefit of indacaterol. [source] The effects of heparin and related molecules on vascular permeability and neutrophil accumulation in rabbit skinBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2002Helen Jones Unfractionated heparin (UH) has been shown to possess a wide range of properties which are potentially anti-inflammatory. Many of these studies, including effects of heparin on adhesion of inflammatory cells to endothelium, have been carried out in vitro. In the present study, we have used radioisotopic techniques to study the effect of UH, and related molecules, on in vivo inflammatory responses (plasma exudation (PE) and PMN accumulation) in rabbit skin induced by cationic proteins, mediators and antigen. Intradermal (i.d.) pretreatment with UH dose-dependently inhibited poly-L-lysine (PLL)-induced responses. The same treatment had no effect on antigen (extract of Alternaria tenuis, AT)-, formyl-methionyl-leucyl-phenylalanine (fMLP)- or leukotriene (LT) B4 -induced responses, although i.d. dextran sulphate (DS) significantly inhibited responses to all of these mediators. High dose (10,000 u kg,1) intravenous UH significantly decreased cutaneous responses to fMLP and LTB4. By comparison, the selectin inhibitor, fucoidin, and DS, were very effective inhibitors of these responses, and of responses to AT and PLL. In contrast to the weak effect in the in vivo studies, UH significantly inhibited in vitro homotypic aggregation of rabbit PMNs, showing that it can modify PMN function. Our data with i.d. UH confirm the important ability of this molecule to interact with and neutralize polycationic peptides in vivo, suggesting that this is a prime role of endogenous heparin. The lack of effect of exogenous heparin on acute inflammatory responses induced by allergen, suggests that cationic proteins are unlikely to be primary mediators of the allergen-induced PE or PMN accumulation. British Journal of Pharmacology (2002) 135, 469,479; doi:10.1038/sj.bjp.0704505 [source] | |||||||||||||||||||||||||