The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
Vincent M Monnier - One of the best experts on this subject based on the ideXlab platform.
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ANAEROBIC VS. AEROBIC PATHWAYS OF CARBONYL AND OXIDANT STRESS IN HUMAN LENS AND SKIN DURING AGING AND IN DIABETES: A COMPARATIVE ANALYSIS
2015Co-Authors: Xingjun Fan, David R Sell, Jianye Zhang, Ina Nemet, Mathilde Theves, Christopher Strauch, Marc K Halushka, Vincent M MonnierAbstract:The effects of anaerobic (lens) vs aerobic (skin) environment on carbonyl and oxidant stress are compared using de novo and existing data on advanced glycation and oxidation products in human crystallins and collagen. Almost all modifications increase with age. Methylglyoxal hydroimidazolones (MG-H1), carboxymethyl-lysine (CML), and carboxyethyl-lysine (CEL) are several folds higher in lens than skin, and markedly increase upon incubation of lens crystallins with 5 mM ascorbic acid. Vice-versa, fructose-lysine, glucosepane crosslinks, glyoxal hydroimidazolones (G-H1), metal catalyzed oxidation (Allysine) and H2O2 dependent modifications (2-aminoapidic acid and methionine sulfoxide) are markedly elevated in skin, but relatively suppressed in the aging lens. In both tissues ornithine is the dominant modification, implicating arginine residues as the principal target of the Maillard reaction in vivo. Diabetes (here mostly type 2 studied) increases significantly fructose-lysine and glucosepane in both tissues (P<0.001) but has surprisingly little effect on the absolute level of most other advanced glycation end products (AGEs). However, diabetes strengthens the Spearman correlation coefficients for age-related accumulation of hydrogen peroxide mediated modifications in the lens. Overall, the data suggest oxoaldehyde stress involving methylglyoxal from either glucose or ascorbate is predominant in the aging non-cataractous lens, while aging skin collagen undergoes combined attack by non-oxidative glucose mediated modifications, as well as those from metal catalyzed oxidation and H2O2
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anaerobic vs aerobic pathways of carbonyl and oxidant stress in human lens and skin during aging and in diabetes a comparative analysis
Free Radical Biology and Medicine, 2010Co-Authors: Xingjun Fan, David R Sell, Jianye Zhang, Ina Nemet, Mathilde Theves, Christopher Strauch, Marc K Halushka, Vincent M MonnierAbstract:Abstract The effects of anaerobic (lens) vs aerobic (skin) environment on carbonyl and oxidant stress are compared using de novo and existing data on advanced glycation and oxidation products in human crystallins and collagen. Almost all modifications increase with age. Methylglyoxal hydroimidazolones, carboxymethyllysine, and carboxyethyllysine are severalfold higher in lens than in skin and markedly increase upon incubation of lens crystallins with 5 mM ascorbic acid. In contrast, fructose-lysine, glucosepane crosslinks, glyoxal hydroimidazolones, metal-catalyzed oxidation (Allysine), and H2O2-dependent modifications (2-aminoapidic acid and methionine sulfoxide) are markedly elevated in skin, but relatively suppressed in the aging lens. In both tissues ornithine is the dominant modification, implicating arginine residues as the principal target of the Maillard reaction in vivo. Diabetes (here mostly type 2 studied) increases significantly fructose-lysine and glucosepane in both tissues (P
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mechanism of lysine oxidation in human lens crystallins during aging and in diabetes
Journal of Biological Chemistry, 2009Co-Authors: Xingjun Fan, Jianye Zhang, Ina Nemet, Mathilde Theves, Christopher Strauch, X Liu, Juan Qian, Frank J Giblin, Vincent M MonnierAbstract:Abstract Oxidative mechanisms during nuclear sclerosis of the lens are poorly understood, in particular metal-catalyzed oxidation. The lysyl oxidation product adipic semialdehyde (Allysine, ALL) and its oxidized end-product 2-aminoadipic acid (2-AAA) were determined as a function of age and presence of diabetes. Surprisingly, whereas both ALL and 2-AAA increased with age and strongly correlated with cataract grade and protein absorbance at 350 nm, only ALL formation but not 2-AAA was increased by diabetes. To clarify the mechanism of oxidation, rabbit lenses were treated with hyperbaric oxygen (HBO) for 48 h, and proteins were analyzed by gas and liquid chromatography mass spectrometry for ALL, 2-AAA, and multiple glycation products. Upon exposure to HBO, rabbit lenses were swollen, and nuclei were yellow. Protein-bound ALL increased 8-fold in the nuclear protein fractions versus controls. A dramatic increase in methyl-glyoxal hydroimidazolone and carboxyethyl-lysine but no increase of 2-AAA occurred, suggesting more drastic conditions are needed to oxidize ALL into 2-AAA. Indeed the latter formed only upon depletion of glutathione and was catalyzed by H2O2. Neither carboxymethyl-lysine nor glyoxal hydroimidazolone, two markers of glyco-/lipoxidation, nor markers of lenticular glycemia (fructose-lysine, glucospane) were elevated by HBO, excluding significant lipid peroxidation and glucose involvement. The findings strongly implicate dicarbonyl/metal catalyzed oxidation of lysine to Allysine, whereby low GSH combined with ascorbate-derived H2O2 likely contributes toward 2-AAA formation, since virtually no 2-AAA formed in the presence of methylglyoxal instead of ascorbate. An important translational conclusion is that chelating agents might help delay nuclear sclerosis.
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aging diabetes and renal failure catalyze the oxidation of lysyl residues to 2 aminoadipic acid in human skin collagen
Annals of the New York Academy of Sciences, 2008Co-Authors: David R Sell, Christopher Strauch, Wei Shen, Vincent M MonnierAbstract:The epsilon-amino group of lysyl residues oxidatively deaminates in the presence of alpha-dicarbonyl sugars and redox-active metals forming alpha-aminoadipic acid-delta-semialdehyde (Allysine; Suyama's hypothesis), which can further oxidize into 2-aminoadipic acid. Here we show that 2-aminoadipic acid is significantly (P 2 nmol/mg collagen).
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2 aminoadipic acid is a marker of protein carbonyl oxidation in the aging human skin effects of diabetes renal failure and sepsis
Biochemical Journal, 2007Co-Authors: David R Sell, Christopher Strauch, Wei Shen, Vincent M MonnierAbstract:We hypothesized that the epsilon-amino group of lysine residues in longlived proteins oxidatively deaminates with age forming the carbonyl compound, Allysine (alpha-aminoadipic acid-delta-semialdehyde), which can further oxidize into 2-aminoadipic acid. In the present study, we measured both products in insoluble human skin collagen from n=117 individuals of age range 10-90 years, of which n=61 and n=56 were non-diabetic and diabetic respectively, and a total of n=61 individuals had either acute or chronic renal failure. Allysine was reduced by borohydride into 6-hydroxynorleucine and both products were measured in acid hydrolysates by selective ion monitoring gas chromatography (GC)-MS. The results showed that 2-aminoadipic acid (P<0.0001), but not 6-hydroxynorleucine (P=0.14), significantly increased with age reaching levels of 1 and 0.3 mmol/mol lysine at late age respectively. Diabetes in the absence of renal failure significantly (P<0.0001) increased 2-aminoadipic acid up to <3 mmol/mol, but not 6-hydroxynorleucine (levels<0.4 mmol/mol, P=0.18). Renal failure even in the absence of diabetes markedly increased levels reaching up to <0.5 and 8 mmol/mol for 6-hydroxynorleucine and 2-aminoadipic acid respectively. Septicaemia significantly (P<0.0001) elevated 2-aminoadipic acid in non-diabetic, but not diabetic individuals, and mildly correlated with other glycoxidation markers, carboxymethyl-lysine and the methylglyoxal-derived products, carboxyethyl-lysine, argpyrimidine and MODIC (methylglyoxal-derived imidazolium cross-link). These results provide support for the presence of metal-catalysed oxidation (the Suyama pathway) in diabetes and the possible activation of myeloperoxidase during sepsis. We conclude that 2-aminoadipic acid is a more reliable marker for protein oxidation than its precursor, Allysine. Its mechanism of formation in each of these conditions needs to be elucidated.
Peter Caravan - One of the best experts on this subject based on the ideXlab platform.
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improving the reactivity of hydrazine bearing mri probes for in vivo imaging of lung fibrogenesis
Chemical Science, 2020Co-Authors: Eman A Akam, Nicholas J Rotile, Eric Abston, Hannah Slattery, I Y Zhou, Michael Lanuti, Peter CaravanAbstract:Pulmonary fibrosis (PF) is the pathologic accumulation of extracellular matrix components in lung tissue that result in scarring following chronic lung injury. PF is typically diagnosed by high resolution computed tomography (HRCT) and/or invasive biopsy. However, HRCT cannot distinguish old injury from active fibrogenesis. We previously demonstrated that Allysine residues on oxidized collagen represent an abundant target during lung fibrogenesis, and that magnetic resonance imaging (MRI) with a small-molecule, gadolinium-containing probe, Gd-Hyd, could specifically detect and stage fibrogenesis in a mouse model. In this work, we present an improved probe, Gd-CHyd, featuring an N,N-dialkyl hydrazine which has an order of magnitude both greater reactivity and affinity for aldehydes. In a paired study in mice with bleomycin induced lung injury we show that the improved reactivity and affinity of Gd-CHyd results in significantly higher lung-to-liver contrast, e.g. 77% higher at 45 min post injection, and slower lung clearance than Gd-Hyd. Gd-CHyd enhanced MRI is >60-fold higher in bleomycin injured mouse lungs compared to uninjured mice. Collectively, our data indicate that enhancing hydrazine reactivity and affinity towards Allysine is an effective strategy to significantly improve molecular MRI probes for lung fibrogenesis.
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68ga nodaga indole an Allysine reactive positron emission tomography probe for molecular imaging of pulmonary fibrogenesis
Journal of the American Chemical Society, 2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Michael Lanuti, Junfeng Wang, Jingyi Sui, Bryan C. Fuchs, Pauline Desogere, Katherine A Grahamoregan, Peter CaravanAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde Allysine, is a universal feature of fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, all...
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68ga nodaga indole an Allysine reactive pet probe for molecular imaging of actively progressive pulmonary fibrogenesis
The Journal of Nuclear Medicine, 2018Co-Authors: Jessica Wahsner, Nicholas J Rotile, Michael Lanuti, Junfeng Wang, Bryan C. Fuchs, Pauline Desogere, Derek J Erstad, Peter CaravanAbstract:260 Objectives: Tissue fibrosis is the accumulation of extracellular matrix molecules that make up scar tissue as a consequence of chronic tissue injury and accounts for nearly half of the deaths in the industrialized world.1 There is an unmet need to develop effective methods for noninvasive detection of actively progressive fibrogenesis. Noninvasive methods that can distinguish active fibrogenesis from stable scar tissue provide indispensable insights for monitoring disease activity or therapeutic responses.Allysine-rich collagen, which promotes its crosslinking is a marker of active fibrogenesis.2,3 Here, we report a novel 68Ga-NODAGA based PET probe that targets Allysine residues in active pulmonary fibrogenesis. Methods: The Allysine-reactive PET probe 68Ga-NODAGA-indole was synthesized by conjugation of a macrocyclic chelator (NODAGA) to a functionalized indole that rapidly forms hydrolytically stable condensation products with aldehydes at physiological pH, followed by labeling with 68Ga. The non-reactive analogue 68Ga-NODAGA-carboline was also synthesized, incapable of undergoing condensation reactions with aldehydes. Both probes were evaluated in the bleomycin mouse (BM) model of pulmonary fibrosis and in healthy animals. In vivo studies include biodistribution and small animal PET-CT imaging after intravenous injection of the active probe 14 days after bleomycin whereas the inactive probe was injected 13 days after bleomycin. Additionally, characterization of collagen/ Allysine content and histology was performed. Pharmacokinetics of the probes were evaluated in healthy mice. Results: The active probe, 68Ga-NODAGA-indole, and the control probe, 68Ga-NODAGA-carboline, showed similar low, nonspecific uptake in the lungs of control mice. In the well-established bleomycin mouse model of pulmonary fibrosis, active probe 68Ga-NODAGA-indole showed 3-fold increased uptake in fibrotic lungs relative to the control probe, 68Ga-NODAGA-carboline, applied in the same disease model. The control probe, 68Ga-NODAGA-carboline, showed similar uptake in the lungs of both fibrotic and control mice. Conclusion: We demonstrated that a small molecule PET probe can be applied for the molecular imaging of active fibrogenesis. Research Support: This project is supported by the National Institutes of Health (EB009062, HL131907, RR029495). JW is supported by the German Research Foundation (DFG). References: 1. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line Sci Transl Med.2013, 5:167sr161. 2. Chen HH, Waghorn PA, Wei L, Tapias LF, Schu Hle DT, Rotile NJ, Jones CM, Looby RJ, Zhao G, Elliott JM, Probst CK, Mino-Kenudson M, Lauwers GY, Tager AM, Tanabe KK, Lanuti M, Fuchs BC, Caravan P. Molecular imaging of oxidized collagen quantifies pulmonary and hepatic fibrogenesis JCI Insight.2017, 2. 3. Waghorn PA, Jones CM, Rotile NJ, Koerner SK, Ferreira DS, Chen HH, Probst CK, Tager AM, Caravan P. Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe Angew Chem Int Ed Engl.2017, 56:9825-9828.
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high sensitivity hplc method for determination of the Allysine concentration in tissue by use of a naphthol derivative
Journal of Chromatography B, 2017Co-Authors: Philip A Waghorn, Bruno L Oliveira, Chloe M Jones, Andrew M Tager, Peter CaravanAbstract:Abstract Common to all fibrotic and metastatic diseases is the uncontrollable remodeling of tissue that leads to the accumulation of fibrous connective tissue components such as collagen and elastin. Build-up of fibrous tissue occurs through the cross-linking of collagen or elastin monomers, which is initiated through the oxidation of lysine residues to form α-aminoadipic-δ-semialdehyde (Allysine). To provide a measure of the extent of collagen oxidation in disease models of fibrosis or metastasis, a rapid, sensitive HPLC method was developed to quantify the amount of Allysine present in tissue. Allysine was reacted with sodium 2-naphthol-7-sulfonate under conditions typically applied for acid hydrolysis of tissues (6 M HCl, 110 °C, 24 h) to prepare AL-NP, a fluorescent bis-naphthol derivative of Allysine. High performance liquid chromatography was applied for analysis of Allysine content. Under optimal reaction and detection conditions, successful separation of AL-NP was achieved with excellent analytical performance attained. Good linear relationship (R 2 = 0.994) between peak area and concentration for AL-NP was attained for 0.35–175 pmol of analyte. A detection limit of 0.02 pmol in the standard sample with a 20 μL injection was achieved for AL-NP, with satisfactory recovery from 88 to 100% determined. The method was applied in the quantification of Allysine in healthy and fibrotic mouse lung tissue, with the fibrotic tissue showing a 2.5 fold increase in the content of Allysine.
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molecular magnetic resonance imaging of lung fibrogenesis with an oxyamine based probe
Angewandte Chemie, 2017Co-Authors: Philip A Waghorn, Chloe M Jones, Andrew M Tager, Nicholas J Rotile, Steffi K Koerner, Diego Dos Santos Ferreira, Howard H Chen, Clemens K Probst, Peter CaravanAbstract:Fibrogenesis is the active production of extracellular matrix in response to tissue injury. In many chronic diseases persistent fibrogenesis results in the accumulation of scar tissue, which can lead to organ failure and death. However, no non-invasive technique exists to assess this key biological process. All tissue fibrogenesis results in the formation of Allysine, which enables collagen cross-linking and leads to tissue stiffening and scar formation. We report herein a novel Allysine-binding gadolinium chelate (GdOA), that can non-invasively detect and quantify the extent of fibrogenesis using magnetic resonance imaging (MRI). We demonstrate that GdOA signal enhancement correlates with the extent of the disease and is sensitive to a therapeutic response.
David R Sell - One of the best experts on this subject based on the ideXlab platform.
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ANAEROBIC VS. AEROBIC PATHWAYS OF CARBONYL AND OXIDANT STRESS IN HUMAN LENS AND SKIN DURING AGING AND IN DIABETES: A COMPARATIVE ANALYSIS
2015Co-Authors: Xingjun Fan, David R Sell, Jianye Zhang, Ina Nemet, Mathilde Theves, Christopher Strauch, Marc K Halushka, Vincent M MonnierAbstract:The effects of anaerobic (lens) vs aerobic (skin) environment on carbonyl and oxidant stress are compared using de novo and existing data on advanced glycation and oxidation products in human crystallins and collagen. Almost all modifications increase with age. Methylglyoxal hydroimidazolones (MG-H1), carboxymethyl-lysine (CML), and carboxyethyl-lysine (CEL) are several folds higher in lens than skin, and markedly increase upon incubation of lens crystallins with 5 mM ascorbic acid. Vice-versa, fructose-lysine, glucosepane crosslinks, glyoxal hydroimidazolones (G-H1), metal catalyzed oxidation (Allysine) and H2O2 dependent modifications (2-aminoapidic acid and methionine sulfoxide) are markedly elevated in skin, but relatively suppressed in the aging lens. In both tissues ornithine is the dominant modification, implicating arginine residues as the principal target of the Maillard reaction in vivo. Diabetes (here mostly type 2 studied) increases significantly fructose-lysine and glucosepane in both tissues (P<0.001) but has surprisingly little effect on the absolute level of most other advanced glycation end products (AGEs). However, diabetes strengthens the Spearman correlation coefficients for age-related accumulation of hydrogen peroxide mediated modifications in the lens. Overall, the data suggest oxoaldehyde stress involving methylglyoxal from either glucose or ascorbate is predominant in the aging non-cataractous lens, while aging skin collagen undergoes combined attack by non-oxidative glucose mediated modifications, as well as those from metal catalyzed oxidation and H2O2
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anaerobic vs aerobic pathways of carbonyl and oxidant stress in human lens and skin during aging and in diabetes a comparative analysis
Free Radical Biology and Medicine, 2010Co-Authors: Xingjun Fan, David R Sell, Jianye Zhang, Ina Nemet, Mathilde Theves, Christopher Strauch, Marc K Halushka, Vincent M MonnierAbstract:Abstract The effects of anaerobic (lens) vs aerobic (skin) environment on carbonyl and oxidant stress are compared using de novo and existing data on advanced glycation and oxidation products in human crystallins and collagen. Almost all modifications increase with age. Methylglyoxal hydroimidazolones, carboxymethyllysine, and carboxyethyllysine are severalfold higher in lens than in skin and markedly increase upon incubation of lens crystallins with 5 mM ascorbic acid. In contrast, fructose-lysine, glucosepane crosslinks, glyoxal hydroimidazolones, metal-catalyzed oxidation (Allysine), and H2O2-dependent modifications (2-aminoapidic acid and methionine sulfoxide) are markedly elevated in skin, but relatively suppressed in the aging lens. In both tissues ornithine is the dominant modification, implicating arginine residues as the principal target of the Maillard reaction in vivo. Diabetes (here mostly type 2 studied) increases significantly fructose-lysine and glucosepane in both tissues (P
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aging diabetes and renal failure catalyze the oxidation of lysyl residues to 2 aminoadipic acid in human skin collagen
Annals of the New York Academy of Sciences, 2008Co-Authors: David R Sell, Christopher Strauch, Wei Shen, Vincent M MonnierAbstract:The epsilon-amino group of lysyl residues oxidatively deaminates in the presence of alpha-dicarbonyl sugars and redox-active metals forming alpha-aminoadipic acid-delta-semialdehyde (Allysine; Suyama's hypothesis), which can further oxidize into 2-aminoadipic acid. Here we show that 2-aminoadipic acid is significantly (P 2 nmol/mg collagen).
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2 aminoadipic acid is a marker of protein carbonyl oxidation in the aging human skin effects of diabetes renal failure and sepsis
Biochemical Journal, 2007Co-Authors: David R Sell, Christopher Strauch, Wei Shen, Vincent M MonnierAbstract:We hypothesized that the epsilon-amino group of lysine residues in longlived proteins oxidatively deaminates with age forming the carbonyl compound, Allysine (alpha-aminoadipic acid-delta-semialdehyde), which can further oxidize into 2-aminoadipic acid. In the present study, we measured both products in insoluble human skin collagen from n=117 individuals of age range 10-90 years, of which n=61 and n=56 were non-diabetic and diabetic respectively, and a total of n=61 individuals had either acute or chronic renal failure. Allysine was reduced by borohydride into 6-hydroxynorleucine and both products were measured in acid hydrolysates by selective ion monitoring gas chromatography (GC)-MS. The results showed that 2-aminoadipic acid (P<0.0001), but not 6-hydroxynorleucine (P=0.14), significantly increased with age reaching levels of 1 and 0.3 mmol/mol lysine at late age respectively. Diabetes in the absence of renal failure significantly (P<0.0001) increased 2-aminoadipic acid up to <3 mmol/mol, but not 6-hydroxynorleucine (levels<0.4 mmol/mol, P=0.18). Renal failure even in the absence of diabetes markedly increased levels reaching up to <0.5 and 8 mmol/mol for 6-hydroxynorleucine and 2-aminoadipic acid respectively. Septicaemia significantly (P<0.0001) elevated 2-aminoadipic acid in non-diabetic, but not diabetic individuals, and mildly correlated with other glycoxidation markers, carboxymethyl-lysine and the methylglyoxal-derived products, carboxyethyl-lysine, argpyrimidine and MODIC (methylglyoxal-derived imidazolium cross-link). These results provide support for the presence of metal-catalysed oxidation (the Suyama pathway) in diabetes and the possible activation of myeloperoxidase during sepsis. We conclude that 2-aminoadipic acid is a more reliable marker for protein oxidation than its precursor, Allysine. Its mechanism of formation in each of these conditions needs to be elucidated.
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cross linking of the extracellular matrix by the maillard reaction in aging and diabetes an update on a puzzle nearing resolution
Annals of the New York Academy of Sciences, 2005Co-Authors: Vincent M Monnier, Georgian T Mustata, Klaus L Biemel, Oliver Reihl, Marcus O Lederer, Dai Zhenyu, David R SellAbstract:Abstract: The aging extracellular matrix is characterized by an age-related increase in insolubilization, yellowing, and stiffening, all of which can be mimicked by the Maillard reaction in vitro. These phenomena are accelerated in metabolic diseases such as diabetes and end-stage renal disease, which have in common with physiological aging the accumulation of various glycation products and cross-links. Eight years ago we concluded that the evidence favored oxidative cross-linking in experimental diabetes [Monnier, V.M. et al. 1996. The mechanism of collagen cross-linking in diabetes: a puzzle nearing completion. Diabetes 45(Suppl. 3): 67-72] and proposed a major role for a putative non-UV active cross-link derived from glucose. Below, we provide an update of the field that leads to the conclusion that, while oxidation might be important for Maillard reaction-mediated cross-linking via Strecker degradation and Allysine formation, the single most important collagen cross-link known to date in diabetes and aging is glucosepane, a lysyl-arginine cross-link that forms under nonoxidative conditions.
Jessica Wahsner - One of the best experts on this subject based on the ideXlab platform.
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68ga nodaga indole an Allysine reactive positron emission tomography probe for molecular imaging of pulmonary fibrogenesis
Journal of the American Chemical Society, 2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Michael Lanuti, Junfeng Wang, Jingyi Sui, Bryan C. Fuchs, Pauline Desogere, Katherine A Grahamoregan, Peter CaravanAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde Allysine, is a universal feature of fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, all...
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68Ga-NODAGA-Indole: An Allysine-Reactive Positron Emission Tomography Probe for Molecular Imaging of Pulmonary Fibrogenesis
2019Co-Authors: Jessica Wahsner, Nicholas J Rotile, Eric Abston, Pauline Désogère, Katherine A. Graham-o’regan, Junfeng Wang, Markus D. Schirmer, Diêgo Dos Santos Ferreira, Jingyi Sui, Bryan C. FuchsAbstract:Oxidized collagen, wherein lysine residues are converted to the aldehyde Allysine, is a universal feature of fibrogenesis, i.e. actively progressive fibrosis. Here we report the small molecule, Allysine-binding positron emission tomography probe, 68Ga-NODAGA-indole, that can noninvasively detect and quantify pulmonary fibrogenesis. We demonstrate that the uptake of 68Ga-NODAGA-indole in actively fibrotic lungs is 7-fold higher than in control groups and that uptake is linearly correlated (R2 = 0.98) with the concentration of lung Allysine
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68ga nodaga indole an Allysine reactive pet probe for molecular imaging of actively progressive pulmonary fibrogenesis
The Journal of Nuclear Medicine, 2018Co-Authors: Jessica Wahsner, Nicholas J Rotile, Michael Lanuti, Junfeng Wang, Bryan C. Fuchs, Pauline Desogere, Derek J Erstad, Peter CaravanAbstract:260 Objectives: Tissue fibrosis is the accumulation of extracellular matrix molecules that make up scar tissue as a consequence of chronic tissue injury and accounts for nearly half of the deaths in the industrialized world.1 There is an unmet need to develop effective methods for noninvasive detection of actively progressive fibrogenesis. Noninvasive methods that can distinguish active fibrogenesis from stable scar tissue provide indispensable insights for monitoring disease activity or therapeutic responses.Allysine-rich collagen, which promotes its crosslinking is a marker of active fibrogenesis.2,3 Here, we report a novel 68Ga-NODAGA based PET probe that targets Allysine residues in active pulmonary fibrogenesis. Methods: The Allysine-reactive PET probe 68Ga-NODAGA-indole was synthesized by conjugation of a macrocyclic chelator (NODAGA) to a functionalized indole that rapidly forms hydrolytically stable condensation products with aldehydes at physiological pH, followed by labeling with 68Ga. The non-reactive analogue 68Ga-NODAGA-carboline was also synthesized, incapable of undergoing condensation reactions with aldehydes. Both probes were evaluated in the bleomycin mouse (BM) model of pulmonary fibrosis and in healthy animals. In vivo studies include biodistribution and small animal PET-CT imaging after intravenous injection of the active probe 14 days after bleomycin whereas the inactive probe was injected 13 days after bleomycin. Additionally, characterization of collagen/ Allysine content and histology was performed. Pharmacokinetics of the probes were evaluated in healthy mice. Results: The active probe, 68Ga-NODAGA-indole, and the control probe, 68Ga-NODAGA-carboline, showed similar low, nonspecific uptake in the lungs of control mice. In the well-established bleomycin mouse model of pulmonary fibrosis, active probe 68Ga-NODAGA-indole showed 3-fold increased uptake in fibrotic lungs relative to the control probe, 68Ga-NODAGA-carboline, applied in the same disease model. The control probe, 68Ga-NODAGA-carboline, showed similar uptake in the lungs of both fibrotic and control mice. Conclusion: We demonstrated that a small molecule PET probe can be applied for the molecular imaging of active fibrogenesis. Research Support: This project is supported by the National Institutes of Health (EB009062, HL131907, RR029495). JW is supported by the German Research Foundation (DFG). References: 1. Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line Sci Transl Med.2013, 5:167sr161. 2. Chen HH, Waghorn PA, Wei L, Tapias LF, Schu Hle DT, Rotile NJ, Jones CM, Looby RJ, Zhao G, Elliott JM, Probst CK, Mino-Kenudson M, Lauwers GY, Tager AM, Tanabe KK, Lanuti M, Fuchs BC, Caravan P. Molecular imaging of oxidized collagen quantifies pulmonary and hepatic fibrogenesis JCI Insight.2017, 2. 3. Waghorn PA, Jones CM, Rotile NJ, Koerner SK, Ferreira DS, Chen HH, Probst CK, Tager AM, Caravan P. Molecular Magnetic Resonance Imaging of Lung Fibrogenesis with an Oxyamine-Based Probe Angew Chem Int Ed Engl.2017, 56:9825-9828.
Angelina M Santini - One of the best experts on this subject based on the ideXlab platform.
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identification of 4 aminomethyl 6 trifluoromethyl 2 phenoxy pyridine derivatives as potent selective and orally efficacious inhibitors of the copper dependent amine oxidase lysyl oxidase like 2 loxl2
Journal of Medicinal Chemistry, 2017Co-Authors: Martin W Rowbottom, Gretchen Bain, Imelda Calderon, Taylor Lasof, David Lonergan, Andiliy G Lai, Fei Huang, Janice Darlington, Patricia Prodanovich, Angelina M SantiniAbstract:LOXL2 catalyzes the oxidative deamination of e-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (Allysine). Condensation with other Allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis. Herein, we describe optimization of an initial hit 2, resulting in identification of racemic-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone 28, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of 28 significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (R,R)-enantiomer 43 (PAT-1251) was selected as the cli...
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Identification of 4‑(Aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine Derivatives as Potent, Selective, and Orally Efficacious Inhibitors of the Copper-Dependent Amine Oxidase, Lysyl Oxidase-Like 2 (LOXL2)
2017Co-Authors: Martin W Rowbottom, Gretchen Bain, Imelda Calderon, Taylor Lasof, David Lonergan, Fei Huang, Janice Darlington, Patricia Prodanovich, Andiliy Lai, Angelina M SantiniAbstract:LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (Allysine). Condensation with other Allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis. Herein, we describe optimization of an initial hit 2, resulting in identification of racemic-trans-(3-((4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)(3-fluoro-4-hydroxypyrrolidin-1-yl)methanone 28, a potent irreversible inhibitor of LOXL2 that is highly selective over LOX and other amine oxidases. Oral administration of 28 significantly reduced fibrosis in a 14-day mouse lung bleomycin model. The (R,R)-enantiomer 43 (PAT-1251) was selected as the clinical compound which has progressed into healthy volunteer Phase 1 trials, making it the “first-in-class” small-molecule LOXL2 inhibitor to enter clinical development