The Experts below are selected from a list of 1623 Experts worldwide ranked by ideXlab platform
Itzik Cooper - One of the best experts on this subject based on the ideXlab platform.
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Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer's disease-like symptoms in animal model.
Cellular and Molecular Life Sciences, 2019Co-Authors: Krishnakumar Viswanathan, Dana Shwartz, Yelena Losev, Elad Arad, Chen Shemesh, Edward Pichinuk, Hamutal Engel, Avi Raveh, Raz Jelinek, Itzik CooperAbstract:Neurofibrillary tangles of the Tau protein and plaques of the amyloid β peptide are hallmarks of Alzheimer’s disease (AD), which is characterized by the conversion of monomeric proteins/peptides into misfolded β-sheet rich fibrils. Halting the fibrillation process and disrupting the existing aggregates are key challenges for AD drug development. Previously, we performed in vitro high-throughput screening for the identification of potent inhibitors of Tau aggregation using a proxy model, a highly aggregation-prone hexapeptide fragment 306VQIVYK311 (termed PHF6) derived from Tau. Here we have characterized a hit molecule from that screen as a modulator of Tau aggregation using in vitro, in silico, and in vivo techniques. This molecule, an anthraquinone derivative named Purpurin, inhibited ~ 50% of PHF6 fibrillization in vitro at equimolar concentration and disassembled pre-formed PHF6 fibrils. In silico studies showed that Purpurin interacted with key residues of PHF6, which are responsible for maintaining its β-sheets conformation. Isothermal titration calorimetry and surface plasmon resonance experiments with PHF6 and full-length Tau (FL-Tau), respectively, indicated that Purpurin interacted with PHF6 predominantly via hydrophobic contacts and displayed a dose-dependent complexation with FL-Tau. Purpurin was non-toxic when fed to Drosophila and it significantly ameliorated the AD-related neurotoxic symptoms of transgenic flies expressing WT-FL human Tau (hTau) plausibly by inhibiting Tau accumulation and reducing Tau phosphorylation. Purpurin also reduced hTau accumulation in cell culture overexpressing hTau. Importantly, Purpurin efficiently crossed an in vitro human blood–brain barrier model. Our findings suggest that Purpurin could be a potential lead molecule for AD therapeutics.
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Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model
Cellular and Molecular Life Sciences, 2019Co-Authors: Guru Krishnakumar Viswanathan, Dana Shwartz, Yelena Losev, Elad Arad, Chen Shemesh, Edward Pichinuk, Hamutal Engel, Avi Raveh, Raz Jelinek, Itzik CooperAbstract:Neurofibrillary tangles of the Tau protein and plaques of the amyloid β peptide are hallmarks of Alzheimer’s disease (AD), which is characterized by the conversion of monomeric proteins/peptides into misfolded β-sheet rich fibrils. Halting the fibrillation process and disrupting the existing aggregates are key challenges for AD drug development. Previously, we performed in vitro high-throughput screening for the identification of potent inhibitors of Tau aggregation using a proxy model, a highly aggregation-prone hexapeptide fragment ^306VQIVYK^311 (termed PHF6) derived from Tau. Here we have characterized a hit molecule from that screen as a modulator of Tau aggregation using in vitro, in silico, and in vivo techniques. This molecule, an anthraquinone derivative named Purpurin, inhibited ~ 50% of PHF6 fibrillization in vitro at equimolar concentration and disassembled pre-formed PHF6 fibrils. In silico studies showed that Purpurin interacted with key residues of PHF6, which are responsible for maintaining its β-sheets conformation. Isothermal titration calorimetry and surface plasmon resonance experiments with PHF6 and full-length Tau (FL-Tau), respectively, indicated that Purpurin interacted with PHF6 predominantly via hydrophobic contacts and displayed a dose-dependent complexation with FL-Tau. Purpurin was non-toxic when fed to Drosophila and it significantly ameliorated the AD-related neurotoxic symptoms of transgenic flies expressing WT-FL human Tau ( h Tau) plausibly by inhibiting Tau accumulation and reducing Tau phosphorylation. Purpurin also reduced h Tau accumulation in cell culture overexpressing h Tau. Importantly, Purpurin efficiently crossed an in vitro human blood–brain barrier model. Our findings suggest that Purpurin could be a potential lead molecule for AD therapeutics.
Lars Rask - One of the best experts on this subject based on the ideXlab platform.
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a genetically engineered Purpurin retinol binding protein hybrid that binds to transthyretin
Biochemical and Biophysical Research Communications, 1992Co-Authors: Håkan Melhus, Lars RaskAbstract:A mini-gene encoding rat retinol-binding protein (RBP) and a cDNA encoding chicken Purpurin were separately transfected into HeLa cells. In contrast to RBP, expressed Purpurin did not bind to transthyretin (TTR). A Purpurin/RBP hybrid protein was constructed by substituting the cDNA sequence encoding the N-terminal 29 amino acids of Purpurin for the corresponding part of RBP. The expressed hybrid molecule bound to the TTR-Sepharose. These results demonstrate that Purpurin does not bind to TTR, that a functional Purpurin/RBP hybrid can be constructed, and that the N-terminal coil of RBP is not required for TTR binding.
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A genetically engineered Purpurin/retinol-binding protein hybrid that binds to transthyretin.
Biochemical and Biophysical Research Communications, 1992Co-Authors: Håkan Melhus, Lars RaskAbstract:A mini-gene encoding rat retinol-binding protein (RBP) and a cDNA encoding chicken Purpurin were separately transfected into HeLa cells. In contrast to RBP, expressed Purpurin did not bind to transthyretin (TTR). A Purpurin/RBP hybrid protein was constructed by substituting the cDNA sequence encoding the N-terminal 29 amino acids of Purpurin for the corresponding part of RBP. The expressed hybrid molecule bound to the TTR-Sepharose. These results demonstrate that Purpurin does not bind to TTR, that a functional Purpurin/RBP hybrid can be constructed, and that the N-terminal coil of RBP is not required for TTR binding.
Günter Bergerhoff - One of the best experts on this subject based on the ideXlab platform.
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konstitution und farbe von alizarin und Purpurin farblacken
Chemische Berichte, 1994Co-Authors: Christianheinrich Wunderlich, Günter BergerhoffAbstract:Constitution and Colour of Alizarin and Purpurin Dyes The colour of madder dyes used as pigment in antiquity and in the last centuries is produced mainly by metal complexes of alizarin (1) and Purpurin (2). Single crystals of aluminium calcium alizarinate and Purpurinate are obtained by two-phase crystallization. X-ray structure determinations show tetranuclear complex molecules with four alizarins which are different from formerly proposed structures. Solutions of 17 metal complexes of alizarin in DMF/Water exhibit UV-Vis spectra the maxima of absorption of which strongly depend on the electronegativity of the metals. A classical explanation for this is given.
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Konstitution und Farbe von Alizarin‐ und Purpurin‐Farblacken
Chemische Berichte, 1994Co-Authors: Christian‐heinrich Wunderlich, Günter BergerhoffAbstract:Constitution and Colour of Alizarin and Purpurin Dyes The colour of madder dyes used as pigment in antiquity and in the last centuries is produced mainly by metal complexes of alizarin (1) and Purpurin (2). Single crystals of aluminium calcium alizarinate and Purpurinate are obtained by two-phase crystallization. X-ray structure determinations show tetranuclear complex molecules with four alizarins which are different from formerly proposed structures. Solutions of 17 metal complexes of alizarin in DMF/Water exhibit UV-Vis spectra the maxima of absorption of which strongly depend on the electronegativity of the metals. A classical explanation for this is given.
Paul Wai-kei Tsang - One of the best experts on this subject based on the ideXlab platform.
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Purpurin Suppresses Candida albicans Biofilm Formation and Hyphal Development
2016Co-Authors: Paul Wai-kei Tsang, Wing-ping FongAbstract:A striking and clinically relevant virulence trait of the human fungal pathogen Candida albicans is its ability to grow and switch reversibly among different morphological forms. Inhibition of yeast-to-hypha transition in C. albicans represents a new paradigm for antifungal intervention. We have previously demonstrated the novel antifungal activity of Purpurin against Candida fungi. In this study, we extended our investigation by examining the in vitro effect of Purpurin on C. albicans morphogenesis and biofilms. The susceptibility of C. albicans biofilms to Purpurin was examined quantitatively by 2,3-bis(2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide reduction assay. Hyphal formation and biofilm ultrastructure were examined qualitatively by scanning electron microscopy (SEM). Quantitative reverse transcription-PCR (qRT-PCR) was used to evaluate the expression of hypha-specific genes and hyphal regulator in Purpurin-treated fungal cells. The results showed that, at sub-lethal concentration (3 mg/ml), Purpurin blocked the yeast-to-hypha transition under hypha-inducing conditions. Purpurin also inhibited C. albicans biofilm formation and reduced the metabolic activity of mature biofilms in a concentration-dependent manner. SEM images showed that Purpurin-treated C. albicans biofilms were scanty and exclusively consisted of aggregates of blastospores. qRT-PCR analyses indicated that Purpurin downregulated the expression of hypha-specific genes (ALS3, ECE1, HWP1, HYR1) and the hyphal regulator RAS1. The data strongly suggested that Purpurin suppressed C. albicans morphogenesis and caused distorted biofilm formation. By virtue of th
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Sub-MIC levels of Purpurin inhibit membrane ATPase-mediated proton efflux activity in the human fungal pathogen Candida albicans
The Journal of Antibiotics, 2014Co-Authors: Paul Wai-kei Tsang, Alan Pak-kin Wong, Han Sung Jung, Wing-ping FongAbstract:Sub-MIC levels of Purpurin inhibit membrane ATPase-mediated proton efflux activity in the human fungal pathogen Candida albicans
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Purpurin Triggers Caspase-Independent Apoptosis in Candida dubliniensis Biofilms
PLoS ONE, 2013Co-Authors: Paul Wai-kei Tsang, Alan Pak-kin Wong, Hai-ping YangAbstract:Candida dubliniensis is an important human fungal pathogen that causes oral infections in patients with AIDS and diabetes mellitus. However, C. Dubliniensis has been frequently reported in bloodstream infections in clinical settings. Like its phylogenetically related virulent species C. albicans, C. Dubliniensis is able to grow and switch between yeast form and filamentous form (hyphae) and develops biofilms on both abiotic and biotic surfaces. Biofilms are recalcitrant to antifungal therapies and C. Dubliniensis readily turns drug resistant upon repeated exposure. More than 80% of infections are associated with biofilms. Suppression of fungal biofilms may therefore represent a viable antifungal strategy with clinical relevance. Here, we report that C. dubliniensis biofilms were inhibited by Purpurin, a natural anthraquinone pigment isolated from madder root. Purpurin inhibited C. dubliniensis biofilm formation in a concentration-dependent manner; while mature biofilms were less susceptible to Purpurin. Scanning electron microscopy (SEM) analysis revealed scanty structure consisting of yeast cells in Purpurin-treated C. dubliniensis biofilms. We sought to delineate the mechanisms of the anti-biofilm activity of Purpurin on C. Dubliniensis. Intracellular ROS levels were significantly elevated in fungal biofilms and depolarization of MMP was evident upon Purpurin treatment in a concentration-dependent manner. DNA degradation was evident. However, no activated metacaspase could be detected. Together, Purpurin triggered metacaspase-independent apoptosis in C. dubliniensis biofilms.
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Purpurin suppresses Candida albicans biofilm formation and hyphal development.
PLoS ONE, 2012Co-Authors: Paul Wai-kei Tsang, H. M. H. N. Bandara, Wing-ping FongAbstract:A striking and clinically relevant virulence trait of the human fungal pathogen Candida albicans is its ability to grow and switch reversibly among different morphological forms. Inhibition of yeast-to-hypha transition in C. albicans represents a new paradigm for antifungal intervention. We have previously demonstrated the novel antifungal activity of Purpurin against Candida fungi. In this study, we extended our investigation by examining the in vitro effect of Purpurin on C. albicans morphogenesis and biofilms. The susceptibility of C. albicans biofilms to Purpurin was examined quantitatively by 2,3-bis(2-methoxy-4-nitro-5-sulfo-phenyl)-2H-tetrazolium-5-carboxanilide reduction assay. Hyphal formation and biofilm ultrastructure were examined qualitatively by scanning electron microscopy (SEM). Quantitative reverse transcription-PCR (qRT-PCR) was used to evaluate the expression of hypha-specific genes and hyphal regulator in Purpurin-treated fungal cells. The results showed that, at sub-lethal concentration (3 µg/ml), Purpurin blocked the yeast-to-hypha transition under hypha-inducing conditions. Purpurin also inhibited C. albicans biofilm formation and reduced the metabolic activity of mature biofilms in a concentration-dependent manner. SEM images showed that Purpurin-treated C. albicans biofilms were scanty and exclusively consisted of aggregates of blastospores. qRT-PCR analyses indicated that Purpurin downregulated the expression of hypha-specific genes (ALS3, ECE1, HWP1, HYR1) and the hyphal regulator RAS1. The data strongly suggested that Purpurin suppressed C. albicans morphogenesis and caused distorted biofilm formation. By virtue of the ability to block these two virulence traits in C. albicans, Purpurin may represent a potential candidate that deserves further investigations in the development of antifungal strategies against this notorious human fungal pathogen in vivo.
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Novel antifungal activity of Purpurin against Candida species in vitro.
Medical Mycology, 2010Co-Authors: Kai Kang, Wing-ping Fong, Paul Wai-kei TsangAbstract:The antifungal activity of Purpurin (1,2,4-trihydroxy-9,10-anthraquinone), a natural red anthraquinone pigment in madder root (Rubia tinctorum L.), was evaluated by a broth microdilution assay against a total of 24 Candida isolates representing six species. The minimum inhibitory concentration (MIC) range of Purpurin was 1.28–5.12 μg/ml. Mechanistic studies using the rhodamine 6G extrusion assay indicated that Purpurin inhibited the energy-dependent efflux pumps of the Candida isolates in a dose-dependent manner. Furthermore, Purpurin demonstrated a dose-dependent depolarization of mitochondrial membrane potential, one of the biochemical checkpoints regulating cell death in eukaryotic cells, suggesting a possible linkage between Purpurin antifungal mechanism and Candida apoptosis.
Håkan Melhus - One of the best experts on this subject based on the ideXlab platform.
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a genetically engineered Purpurin retinol binding protein hybrid that binds to transthyretin
Biochemical and Biophysical Research Communications, 1992Co-Authors: Håkan Melhus, Lars RaskAbstract:A mini-gene encoding rat retinol-binding protein (RBP) and a cDNA encoding chicken Purpurin were separately transfected into HeLa cells. In contrast to RBP, expressed Purpurin did not bind to transthyretin (TTR). A Purpurin/RBP hybrid protein was constructed by substituting the cDNA sequence encoding the N-terminal 29 amino acids of Purpurin for the corresponding part of RBP. The expressed hybrid molecule bound to the TTR-Sepharose. These results demonstrate that Purpurin does not bind to TTR, that a functional Purpurin/RBP hybrid can be constructed, and that the N-terminal coil of RBP is not required for TTR binding.
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A genetically engineered Purpurin/retinol-binding protein hybrid that binds to transthyretin.
Biochemical and Biophysical Research Communications, 1992Co-Authors: Håkan Melhus, Lars RaskAbstract:A mini-gene encoding rat retinol-binding protein (RBP) and a cDNA encoding chicken Purpurin were separately transfected into HeLa cells. In contrast to RBP, expressed Purpurin did not bind to transthyretin (TTR). A Purpurin/RBP hybrid protein was constructed by substituting the cDNA sequence encoding the N-terminal 29 amino acids of Purpurin for the corresponding part of RBP. The expressed hybrid molecule bound to the TTR-Sepharose. These results demonstrate that Purpurin does not bind to TTR, that a functional Purpurin/RBP hybrid can be constructed, and that the N-terminal coil of RBP is not required for TTR binding.
