The Experts below are selected from a list of 180 Experts worldwide ranked by ideXlab platform
Balaram Ghosh - One of the best experts on this subject based on the ideXlab platform.
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Mepacrine treatment attenuates allergic airway remodeling segregated from airway inflammation in mice.
International Immunopharmacology, 2010Co-Authors: Tanveer Ahmad, Kanika Hasija, Ulaganathan Mabalirajan, Balaram Ghosh, Anurag AgrawalAbstract:Abstract Asthma is a chronic airway disease characterized by increased airway hyperresponsiveness, airway inflammation, and airway remodeling including collagen deposition in subepithelial regions. We have shown earlier that Mepacrine has anti-inflammatory activity and decreased the features of airway remodeling in a subacute model of asthma, when administered during the inflammatory phase. But it was not clear whether the reduction of airway remodeling by Mepacrine was a direct effect or indirectly related to the reduction in the airway inflammation. In this study, we determined the effect of Mepacrine on airway remodeling and airway hyperresponsiveness (AHR) in a chronic model of asthma which showed the features of airway inflammation in the initial stage (inflammation predominant stage) and airway remodeling with mild airway inflammation in a later stage (remodeling predominant stage). Mepacrine was administered only in the later stage that more accurately simulates human asthma, where airway remodeling already exists at the time of diagnosis. The remodeling predominant stage was associated with high levels of Th2 cytokines like IL-4 and IL-13, increase in the levels of profibrotic mediators such as arginase and TGF-β, and increased collagen deposition. These were efficiently attenuated by Mepacrine treatment and led to a significant reduction in AHR. Thus, we conclude from this study that Mepacrine has direct effects on established airway remodeling independent of its anti-inflammatory effects.
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Mepacrine inhibits subepithelial fibrosis by reducing the expression of arginase and tgf β1 in an extended subacute mouse model of allergic asthma
American Journal of Physiology-lung Cellular and Molecular Physiology, 2009Co-Authors: Ulaganathan Mabalirajan, Jyotirmoi Aich, Anurag K Agrawal, Balaram GhoshAbstract:Asthma is a dynamic disorder of airway inflammation and airway remodeling with an imbalance in T helper type 1 (Th 1 )/Th 2 immune response. Increased Th 2 cytokines such as IL-4 and IL-13 induce arginase either directly or indirectly through transforming growth factor-β 1 (TGF-β 1 ) and lead to subepithelial fibrosis, which is a crucial component of airway remodeling. Synthetic antimalarials have been reported to have immunomodulatory properties. Mepacrine is known for its reduction of airway inflammation in short-term allergen challenge model by reducing Th 2 cytokines and cysteinyl leukotrienes, which has an important role in the development of airway remodeling features. Therefore, we hypothesized that Mepacrine may reduce airway remodeling. For this, extended subacute ovalbumin mice model of asthma was developed; these mice showed an increased expression of profibrotic mediators, subepithelial fibrosis, and goblet cell metaplasia along with airway inflammation, increased Th 2 cytokines, allergen-specific IgE, IgG 1 , increased cytosolic PLA 2 (cPLA 2 ), and airway hyperresponsiveness. Presence of intraepithelial eosinophils and significant TGF-β 1 expression in subepithelial mesenchymal regions by repeated allergen exposures indicate that asthmatic mice of this study have developed human mimicking as well as late stages of asthma. However, Mepacrine treatment decreased Th 2 cytokines and subepithelial fibrosis and alleviated asthma features. These reductions by Mepacrine were associated with a decrease in levels and expression of TGF-β 1 and the reduction in activity, expression of arginase in lung cytosol, and immunolocalization in inflammatory cells present in perivascular and peribronchial regions. These results suggest that Mepacrine might reduce the development of subepithelial fibrosis by reducing the arginase and TGF-β 1 . These effects of Mepacrine likely underlie its antiairway remodeling action in asthma.
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Mepacrine alleviates airway hyperresponsiveness and airway inflammation in a mouse model of asthma
International Immunopharmacology, 2008Co-Authors: Arjun Ram, Ulaganathan Mabalirajan, Shashi Kant Singh, Vijay P Singh, Balaram GhoshAbstract:Asthma is a multifactorial respiratory disease. Though its incidence is increasing rapidly all over the world, the available therapeutic strategies are neither sufficient nor safe for long term use. Mepacrine, a known antimalarial drug, has been shown to possess antioxidant, anti-inflammatory, platelet anti-aggregant, and PLA2 inhibitory activities. However, its possible use in asthma has not been studied yet. The objective of this study was to investigate the anti-asthmatic property of Mepacrine using a mouse model of asthma. To accomplish this, male BALB/c mice were sensitized and challenged with ovalbumin and treated with increasing concentrations of Mepacrine. Airway hyperresponsiveness (AHR) to methacholine was assessed using unrestrained whole body plethysmography. Mepacrine (1 mg/kg) has shown marked attenuation of AHR. Cytokines such as IL-4, IL-5, IL-13 and IFN-gamma and OVA-specific IgE levels were measured in BAL (bronchoalveloar lavage) fluid and sera, respectively. Mepacrine effectively reduced the rise in IL-4, IL-5, IL-13, and OVA-specific IgE and restored IFN-gamma levels. Mepacrine also significantly prevented the increase of sPLA2 (secretory phospholipase A2) activity in BAL fluid supernatant and Cys-LT (cysteinyl leukotrienes) in lung tissue homogenates of asthmatic mice. In addition, Mepacrine treatment reduced BAL fluid eosinophilia and signs of allergic airway inflammation such as perivascular and peribronchial distribution of inflammatory cells. These findings indicate that Mepacrine reduces the asthmatic features in ovalbumin induced asthma by acting on PLA2-Cys-LT axis. Thus, it could be useful for the development of better asthma therapy.
R L Krauthsiegel - One of the best experts on this subject based on the ideXlab platform.
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biological evaluation and x ray co crystal structures of cyclohexylpyrrolidine ligands for trypanothione reductase an enzyme from the redox metabolism of trypanosoma
ChemMedChem, 2018Co-Authors: R De Gasparo, R L Krauthsiegel, E Brodbeckpersch, S Bryson, N B Hentzen, Marcel Kaiser, Francois DiederichAbstract:The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (K; i; ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half-maximal inhibitory concentration, IC; 50; ) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X-ray co-crystal structures confirmed the binding of the ligands to the hydrophobic wall of the "Mepacrine binding site" with the new, solubility-providing vectors oriented toward the surface of the large active site.
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inhibition of trypanosoma cruzi trypanothione reductase by acridines kinetic studies and structure activity relationships
Journal of Medicinal Chemistry, 1999Co-Authors: S Bonse, C Santellirouvier, J Barbe, R L KrauthsiegelAbstract:Series of 9-amino and 9-thioacridines have been synthesized and studied as inhibitors of trypanothione reductase (TR) from Trypanosoma cruzi, the causative agent of Chagas' disease. The compounds are structural analogues of the acridine drug Mepacrine (quinacrine), which is a competitive inhibitor of the parasite enzyme, but not of human glutathione reductase, the closest related host enzyme. The 9-aminoacridines yielded apparent Ki values for competitive inhibition between 5 and 43 μM. The most effective inhibitors were those with the methoxy and chlorine substituents of Mepacrine and NH2 or NHCH(CH3)(CH2)4N(Et)2 at C9. Detailed kinetic analyses revealed that in the case of 9-aminoacridines more than one inhibitor molecule can bind to the enzyme. In contrast, the 9-thioacridine derivatives inhibit TR with mixed-type kinetics. The kinetic data are discussed in light of the three-dimensional structure of the TR−Mepacrine complex. The conclusion that structurally very similar acridine compounds can give ris...
Ulaganathan Mabalirajan - One of the best experts on this subject based on the ideXlab platform.
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Mepacrine treatment attenuates allergic airway remodeling segregated from airway inflammation in mice.
International Immunopharmacology, 2010Co-Authors: Tanveer Ahmad, Kanika Hasija, Ulaganathan Mabalirajan, Balaram Ghosh, Anurag AgrawalAbstract:Abstract Asthma is a chronic airway disease characterized by increased airway hyperresponsiveness, airway inflammation, and airway remodeling including collagen deposition in subepithelial regions. We have shown earlier that Mepacrine has anti-inflammatory activity and decreased the features of airway remodeling in a subacute model of asthma, when administered during the inflammatory phase. But it was not clear whether the reduction of airway remodeling by Mepacrine was a direct effect or indirectly related to the reduction in the airway inflammation. In this study, we determined the effect of Mepacrine on airway remodeling and airway hyperresponsiveness (AHR) in a chronic model of asthma which showed the features of airway inflammation in the initial stage (inflammation predominant stage) and airway remodeling with mild airway inflammation in a later stage (remodeling predominant stage). Mepacrine was administered only in the later stage that more accurately simulates human asthma, where airway remodeling already exists at the time of diagnosis. The remodeling predominant stage was associated with high levels of Th2 cytokines like IL-4 and IL-13, increase in the levels of profibrotic mediators such as arginase and TGF-β, and increased collagen deposition. These were efficiently attenuated by Mepacrine treatment and led to a significant reduction in AHR. Thus, we conclude from this study that Mepacrine has direct effects on established airway remodeling independent of its anti-inflammatory effects.
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Mepacrine inhibits subepithelial fibrosis by reducing the expression of arginase and tgf β1 in an extended subacute mouse model of allergic asthma
American Journal of Physiology-lung Cellular and Molecular Physiology, 2009Co-Authors: Ulaganathan Mabalirajan, Jyotirmoi Aich, Anurag K Agrawal, Balaram GhoshAbstract:Asthma is a dynamic disorder of airway inflammation and airway remodeling with an imbalance in T helper type 1 (Th 1 )/Th 2 immune response. Increased Th 2 cytokines such as IL-4 and IL-13 induce arginase either directly or indirectly through transforming growth factor-β 1 (TGF-β 1 ) and lead to subepithelial fibrosis, which is a crucial component of airway remodeling. Synthetic antimalarials have been reported to have immunomodulatory properties. Mepacrine is known for its reduction of airway inflammation in short-term allergen challenge model by reducing Th 2 cytokines and cysteinyl leukotrienes, which has an important role in the development of airway remodeling features. Therefore, we hypothesized that Mepacrine may reduce airway remodeling. For this, extended subacute ovalbumin mice model of asthma was developed; these mice showed an increased expression of profibrotic mediators, subepithelial fibrosis, and goblet cell metaplasia along with airway inflammation, increased Th 2 cytokines, allergen-specific IgE, IgG 1 , increased cytosolic PLA 2 (cPLA 2 ), and airway hyperresponsiveness. Presence of intraepithelial eosinophils and significant TGF-β 1 expression in subepithelial mesenchymal regions by repeated allergen exposures indicate that asthmatic mice of this study have developed human mimicking as well as late stages of asthma. However, Mepacrine treatment decreased Th 2 cytokines and subepithelial fibrosis and alleviated asthma features. These reductions by Mepacrine were associated with a decrease in levels and expression of TGF-β 1 and the reduction in activity, expression of arginase in lung cytosol, and immunolocalization in inflammatory cells present in perivascular and peribronchial regions. These results suggest that Mepacrine might reduce the development of subepithelial fibrosis by reducing the arginase and TGF-β 1 . These effects of Mepacrine likely underlie its antiairway remodeling action in asthma.
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Mepacrine alleviates airway hyperresponsiveness and airway inflammation in a mouse model of asthma
International Immunopharmacology, 2008Co-Authors: Arjun Ram, Ulaganathan Mabalirajan, Shashi Kant Singh, Vijay P Singh, Balaram GhoshAbstract:Asthma is a multifactorial respiratory disease. Though its incidence is increasing rapidly all over the world, the available therapeutic strategies are neither sufficient nor safe for long term use. Mepacrine, a known antimalarial drug, has been shown to possess antioxidant, anti-inflammatory, platelet anti-aggregant, and PLA2 inhibitory activities. However, its possible use in asthma has not been studied yet. The objective of this study was to investigate the anti-asthmatic property of Mepacrine using a mouse model of asthma. To accomplish this, male BALB/c mice were sensitized and challenged with ovalbumin and treated with increasing concentrations of Mepacrine. Airway hyperresponsiveness (AHR) to methacholine was assessed using unrestrained whole body plethysmography. Mepacrine (1 mg/kg) has shown marked attenuation of AHR. Cytokines such as IL-4, IL-5, IL-13 and IFN-gamma and OVA-specific IgE levels were measured in BAL (bronchoalveloar lavage) fluid and sera, respectively. Mepacrine effectively reduced the rise in IL-4, IL-5, IL-13, and OVA-specific IgE and restored IFN-gamma levels. Mepacrine also significantly prevented the increase of sPLA2 (secretory phospholipase A2) activity in BAL fluid supernatant and Cys-LT (cysteinyl leukotrienes) in lung tissue homogenates of asthmatic mice. In addition, Mepacrine treatment reduced BAL fluid eosinophilia and signs of allergic airway inflammation such as perivascular and peribronchial distribution of inflammatory cells. These findings indicate that Mepacrine reduces the asthmatic features in ovalbumin induced asthma by acting on PLA2-Cys-LT axis. Thus, it could be useful for the development of better asthma therapy.
Carl W. Jackson - One of the best experts on this subject based on the ideXlab platform.
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A flow cytometric assay using Mepacrine for study of uptake and release of platelet dense granule contents.
British journal of haematology, 1995Co-Authors: Judith E. Wall, Marleen Buijs-wilts, Julie T. Arnold, Winfred C. Wang, Melanie M. White, Lisa K. Jennings, Carl W. JacksonAbstract:Diagnosis of platelet dense granule storage pool disease and release defects at present requires a combination of studies including lumiaggregometry, conventional platelet aggregation, radioactive serotonin uptake and release, and electron microscopy. Flow cytometric methods have been developed to study platelet activation, aggregation, and alpha-granule protein release. Here, we have investigated the use of flow cytometry for analysis of platelet dense granule content uptake and release using Mepacrine as a fluorescent marker. Mepacrine (quinacrine) is rapidly taken up and localized in dense granules of platelets. For the assay, as little as 20 microliters of blood from a fingerstick collected without anticoagulant or venous blood collected in 3.8% sodium citrate were diluted 1:40 with 2 ml Hanks balanced salt solution (BSS). 300 microliters of this cell suspension were incubated with Mepacrine alone, or simultaneously with a mouse monoclonal antibody to human platelet glycoprotein IIb (Tab), used as a platelet-specific marker. The bound monoclonal antibody was then indirectly labelled with the fluorochrome, RED670. 100 microliters of the sample were further diluted with Hanks BSS for one- or two-colour flow cytometric analysis. To verify that Mepacrine uptake was related to platelet dense granule content, platelets of beige mice, a strain with dense granule deficiency, were examined. Their Mepacrine uptake was substantially decreased compared to that of normal mice. Decreased Mepacrine uptake also was demonstrated in platelets of a patient with Hermansky-Pudlak syndrome in which a deficiency of platelet dense granules is characteristic. In both human and mouse platelets, Mepacrine uptake was proportional to platelet size. Thrombin induced Mepacrine release in a dose-dependent manner from 0.003 to 0.4 U/ml. Therefore both platelet uptake and release of Mepacrine can be readily detected by flow cytometry. Flow cytometry provides an attractive alternative to aggregation and radioactive serotonin as methods to study defects in platelet dense granule function.
Francisco A Uzal - One of the best experts on this subject based on the ideXlab platform.
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potential therapeutic effects of Mepacrine against clostridium perfringens enterotoxin in a mouse model of enterotoxemia
Infection and Immunity, 2019Co-Authors: Mauricio A Navarro, John C Freedman, Bruce A Mcclane, Archana Shrestha, Juliann Beingesser, Francisco A UzalAbstract:Clostridium perfringens enterotoxin (CPE) is a pore-forming toxin that causes the symptoms of common bacterial food poisoning and several non-foodborne human gastrointestinal diseases, including antibiotic-associated diarrhea and sporadic diarrhea. In some cases, CPE-mediated disease can be very severe or fatal due to the involvement of enterotoxemia. Therefore, the development of potential therapeutics against CPE action during enterotoxemia is warranted. Mepacrine, an acridine derivative drug with broad-spectrum effects on pores and channels in mammalian membranes, has been used to treat protozoal intestinal infections in human patients. A previous study showed that the presence of Mepacrine inhibits CPE-induced pore formation and activity in enterocyte-like Caco-2 cells, reducing the cytotoxicity caused by this toxin in vitro Whether Mepacrine is similarly protective against CPE action in vivo has not been tested. When the current study evaluated whether Mepacrine protects against CPE-induced death and intestinal damage using a murine ligated intestinal loop model, Mepacrine protected mice from the enterotoxemic lethality caused by CPE. This protection was accompanied by a reduction in the severity of intestinal lesions induced by the toxin. Mepacrine did not reduce CPE pore formation in the intestine but inhibited absorption of the toxin into the blood of some mice. Protection from enterotoxemic death correlated with the ability of this drug to reduce CPE-induced hyperpotassemia. These in vivo findings, coupled with previous in vitro studies, support Mepacrine as a potential therapeutic against CPE-mediated enterotoxemic disease.