The Experts below are selected from a list of 23562 Experts worldwide ranked by ideXlab platform
T. J. Thomas - One of the best experts on this subject based on the ideXlab platform.
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Nanoparticle strategies for cancer therapeutics: Nucleic acids, Polyamines, bovine serum amine oxidase and iron oxide nanoparticles (Review)
International Journal of Oncology, 2015Co-Authors: Emanuela Agostinelli, Fabio Vianello, Thresia Thomas, Giuseppe Magliulo, T. J. ThomasAbstract:Nanotechnology for cancer gene therapy is an emerging field. Nucleic acids, Polyamine analogues and cytotoxic products of Polyamine oxidation, generated in situ by an enzyme-catalyzed reaction, can be developed for nanotechnology-based cancer therapeutics with reduced systemic toxicity and improved therapeutic efficacy. Nucleic acid-based gene therapy approaches depend on the compaction of DNA/RNA to nanoparticles and Polyamine analogues are excellent agents for the condensation of nucleic acids to nanoparticles. Polyamines and amine oxidases are found in higher levels in tumours compared to that of normal tissues. Therefore, the metabolism of Polyamines spermidine and spermine, and their diamine precursor, putrescine, can be targets for antineoplastic therapy since these naturally occurring alkylamines are essential for normal mammalian cell growth. Intracellular Polyamine concentrations are maintained at a cell type-specific set point through the coordinated and highly regulated interplay between biosynthesis, transport, and catabolism. In particular, Polyamine catabolism involves copper-containing amine oxidases. Several studies showed an important role of these enzymes in developmental and disease-related processes in animals through the control of Polyamine homeostasis in response to normal cellular signals, drug treatment, and environmental and/or cellular stress. The production of toxic aldehydes and reactive oxygen species (ROS), H2O2 in particular, by these oxidases suggests a mechanism by which amine oxidases can be exploited as antineoplastic drug targets. The combination of bovine serum amine oxidase (BSAO) and Polyamines prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. The findings described herein suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death. Consequently, superparamagnetic nanoparticles or other advanced nanosystem based on directed nucleic acid assemblies, Polyamine-induced DNA condensation, and bovine serum amine oxidase may be proposed for futuristic anticancer therapy utilizing nucleic acids, Polyamines and BSAO. BSAO based nanoparticles can be employed for the generation of cytotoxic Polyamine metabolites.
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Polyamine analogues bind human serum albumin
Biomacromolecules, 2007Co-Authors: R Beauchemin, T. J. Thomas, Thresia Thomas, C N Nsoukpoekossi, R Carpentier, H A TajmirriahiAbstract:Polyamine analogues show antitumor activity in experimental models and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of Polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several Polyamine analogues such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) in aqueous solution at physiological conditions, using a constant protein concentration and various Polyamine contents (μM to mM). FTIR, UV-visible and CD spectroscopic methods were used to determine the Polyamine binding mode and the effects of Polyamine complexation on protein stability and secondary structure. Structural analysis showed that Polyamines bind non-specifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 × 103 M−1, KBE-333 = 5.63 × 102 M−1 and KBE-3333 = 3.66 × 102 M−1. The protein secondary structure showed major alterations with reduction of α-helix from 55% (free protein) to 43–50% and increase of β-sheet from 17% (free protein) to 29–36% in the 333-, BE-333- and BE-3333 complexes, indicating a partial protein unfolding upon Polyamine interaction. HSA structure was less perturbed by Polyamine analogues than those of the biogenic Polyamines.
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Polyamine metabolism and cancer
Journal of Cellular and Molecular Medicine, 2003Co-Authors: Thresia Thomas, T. J. ThomasAbstract:Polyamines are aliphatic cations present in all cells. In normal cells, Polyamine levels are intricately controlled by biosynthetic and catabolic enzymes. The biosynthetic enzymes are ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase, and spermine synthase. The catabolic enzymes include spermidine/spermine acetyltransferase, flavin containing Polyamine oxidase, copper containing diamine oxidase, and possibly other amine oxidases. Multiple abnormalities in the control of Polyamine metabolism and uptake might be responsible for increased levels of Polyamines in cancer cells as compared to that of normal cells. This review is designed to look at the current research in Polyamine biosynthesis, catabolism, and transport pathways, enumerate the functions of Polyamines, and assess the potential for using Polyamine metabolism or function as targets for cancer therapy.
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dna condensation by Polyamines a laser light scattering study of structural effects
Biochemistry, 2001Co-Authors: Veena Vijayanathan, Thresia Thomas, And Akira Shirahata, T. J. ThomasAbstract:Polyamines such as spermidine and spermine are abundant in living cells and are believed to aid in the dense packaging of cellular DNA. DNA condensation is a prerequisite for the transport of gene vectors in living cells. To elucidate the structural features of Polyamines governing DNA condensation, we studied the collapse of λ-DNA by spermine and a series of its homologues, H2N(CH2)3NH(CH2)n=2-12NH(CH2)3NH2 (n = 4 for spermine), using static and dynamic light scattering techniques. All Polyamines provoked DNA condensation; however, their efficacy varied with the structural geometry of the Polyamine. In 10 mM sodium cacodylate buffer, the EC50 values for DNA condensation were comparable (4 ± 1 μM) for spermine homologues with n = 4−8, whereas the lower and higher homologues provoked DNA condensation at higher EC50 values. The EC50 values increased with an increase in the monovalent ion (Na+) concentration in the buffer. The slope of a plot of log [EC50(Polyamine4+)] against log [Na+] was ∼1.5 for polyamin...
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Polyamines in cell growth and cell death molecular mechanisms and therapeutic applications
Cellular and Molecular Life Sciences, 2001Co-Authors: T Thomas, T. J. ThomasAbstract:Polyamines are aliphatic cations with multiple functions and are essential for life. Cellular Polyamine levels are regulated by multiple pathways such as synthesis from amino acid precursors, cellular uptake mechanisms that salvage Polyamines from diet and intestinal microorganisms, as well as stepwise degradation and efflux. Investigations using Polyamine biosynthetic inhibitors indicate that alterations in cellular Polyamine levels modulate normal and cancer cell growth. Studies using transgenic mice overexpressing Polyamine biosynthetic enzymes support a role of Polyamines in carcinogenesis. Many, if not all, signal transduction pathways intersect with Polyamine biosynthetic pathways and the regulation of intracellular Polyamine levels. Direct binding of Polyamines to DNA and their ability to modulate DNA-protein interactions appear to be important in the molecular mechanisms of Polyamine action in cell proliferation. Consistent with the role of Polyamines as facilitators of cell growth, several studies have shown their ability to protect cells from apoptosis. However, Polyamines also have a role in facilitating cell death. The basis of these diverse cellular responses is currently not known. Cell death response might be partly mediated by the production of hydrogen peroxide during Polyamine catabolism. In addition, the ability of Polyamines to alter DNA-protein and protein-protein interactions might be disruptive to cellular functions, when abnormally high levels are accumulated due to defects in Polyamine catabolic or efflux pathways. A large body of data indicates that Polyamine pathway can be a molecular target for therapeutic intervention in several types cancers. Inhibitors of biosynthesis, Polyamine analogues as well as oligonucleotide/Polyamine analogue combinations are promising drug candidates for chemoprevention and/or treatment of cancer.
Thresia Thomas - One of the best experts on this subject based on the ideXlab platform.
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Nanoparticle strategies for cancer therapeutics: Nucleic acids, Polyamines, bovine serum amine oxidase and iron oxide nanoparticles (Review)
International Journal of Oncology, 2015Co-Authors: Emanuela Agostinelli, Fabio Vianello, Thresia Thomas, Giuseppe Magliulo, T. J. ThomasAbstract:Nanotechnology for cancer gene therapy is an emerging field. Nucleic acids, Polyamine analogues and cytotoxic products of Polyamine oxidation, generated in situ by an enzyme-catalyzed reaction, can be developed for nanotechnology-based cancer therapeutics with reduced systemic toxicity and improved therapeutic efficacy. Nucleic acid-based gene therapy approaches depend on the compaction of DNA/RNA to nanoparticles and Polyamine analogues are excellent agents for the condensation of nucleic acids to nanoparticles. Polyamines and amine oxidases are found in higher levels in tumours compared to that of normal tissues. Therefore, the metabolism of Polyamines spermidine and spermine, and their diamine precursor, putrescine, can be targets for antineoplastic therapy since these naturally occurring alkylamines are essential for normal mammalian cell growth. Intracellular Polyamine concentrations are maintained at a cell type-specific set point through the coordinated and highly regulated interplay between biosynthesis, transport, and catabolism. In particular, Polyamine catabolism involves copper-containing amine oxidases. Several studies showed an important role of these enzymes in developmental and disease-related processes in animals through the control of Polyamine homeostasis in response to normal cellular signals, drug treatment, and environmental and/or cellular stress. The production of toxic aldehydes and reactive oxygen species (ROS), H2O2 in particular, by these oxidases suggests a mechanism by which amine oxidases can be exploited as antineoplastic drug targets. The combination of bovine serum amine oxidase (BSAO) and Polyamines prevents tumour growth, particularly well if the enzyme has been conjugated with a biocompatible hydrogel polymer. The findings described herein suggest that enzymatically formed cytotoxic agents activate stress signal transduction pathways, leading to apoptotic cell death. Consequently, superparamagnetic nanoparticles or other advanced nanosystem based on directed nucleic acid assemblies, Polyamine-induced DNA condensation, and bovine serum amine oxidase may be proposed for futuristic anticancer therapy utilizing nucleic acids, Polyamines and BSAO. BSAO based nanoparticles can be employed for the generation of cytotoxic Polyamine metabolites.
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biogenic and synthetic Polyamines bind bovine serum albumin
Biomacromolecules, 2010Co-Authors: S Dubeau, Thresia Thomas, P Bourassa, H A TajmirriahiAbstract:Biogenic Polyamines are found to modulate protein synthesis at different levels, while Polyamine analogues have shown major antitumor activity in multiple experimental models, including breast cancer. The aim of this study was to examine the interaction of bovine serum albumin (BSA) with biogenic Polyamines, spermine and spermidine, and Polyamine analogues 3,7,11,15-tetrazaheptadecane·4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane·5HCl (BE-3333) in aqueous solution at physiological conditions. FTIR, UV−visible, CD, and fluorescence spectroscopic methods were used to determine the Polyamine binding mode and the effects of Polyamine complexation on protein stability and secondary structure. Structural analysis showed that Polyamines bind BSA via both hydrophilic and hydrophobic interactions. Stronger Polyamine−protein complexes formed with biogenic than synthetic Polyamines with overall binding constants of Kspm = 3.56 (±0.5) × 105 M−1, Kspmd = 1.77 (±0.4) × 105 M−1, KBE-333 = 1.11 (±0.3) × 104 M−1 and KB...
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Polyamine analogues bind human serum albumin
Biomacromolecules, 2007Co-Authors: R Beauchemin, T. J. Thomas, Thresia Thomas, C N Nsoukpoekossi, R Carpentier, H A TajmirriahiAbstract:Polyamine analogues show antitumor activity in experimental models and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of Polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several Polyamine analogues such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) in aqueous solution at physiological conditions, using a constant protein concentration and various Polyamine contents (μM to mM). FTIR, UV-visible and CD spectroscopic methods were used to determine the Polyamine binding mode and the effects of Polyamine complexation on protein stability and secondary structure. Structural analysis showed that Polyamines bind non-specifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 × 103 M−1, KBE-333 = 5.63 × 102 M−1 and KBE-3333 = 3.66 × 102 M−1. The protein secondary structure showed major alterations with reduction of α-helix from 55% (free protein) to 43–50% and increase of β-sheet from 17% (free protein) to 29–36% in the 333-, BE-333- and BE-3333 complexes, indicating a partial protein unfolding upon Polyamine interaction. HSA structure was less perturbed by Polyamine analogues than those of the biogenic Polyamines.
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Polyamine metabolism and cancer
Journal of Cellular and Molecular Medicine, 2003Co-Authors: Thresia Thomas, T. J. ThomasAbstract:Polyamines are aliphatic cations present in all cells. In normal cells, Polyamine levels are intricately controlled by biosynthetic and catabolic enzymes. The biosynthetic enzymes are ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase, and spermine synthase. The catabolic enzymes include spermidine/spermine acetyltransferase, flavin containing Polyamine oxidase, copper containing diamine oxidase, and possibly other amine oxidases. Multiple abnormalities in the control of Polyamine metabolism and uptake might be responsible for increased levels of Polyamines in cancer cells as compared to that of normal cells. This review is designed to look at the current research in Polyamine biosynthesis, catabolism, and transport pathways, enumerate the functions of Polyamines, and assess the potential for using Polyamine metabolism or function as targets for cancer therapy.
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dna condensation by Polyamines a laser light scattering study of structural effects
Biochemistry, 2001Co-Authors: Veena Vijayanathan, Thresia Thomas, And Akira Shirahata, T. J. ThomasAbstract:Polyamines such as spermidine and spermine are abundant in living cells and are believed to aid in the dense packaging of cellular DNA. DNA condensation is a prerequisite for the transport of gene vectors in living cells. To elucidate the structural features of Polyamines governing DNA condensation, we studied the collapse of λ-DNA by spermine and a series of its homologues, H2N(CH2)3NH(CH2)n=2-12NH(CH2)3NH2 (n = 4 for spermine), using static and dynamic light scattering techniques. All Polyamines provoked DNA condensation; however, their efficacy varied with the structural geometry of the Polyamine. In 10 mM sodium cacodylate buffer, the EC50 values for DNA condensation were comparable (4 ± 1 μM) for spermine homologues with n = 4−8, whereas the lower and higher homologues provoked DNA condensation at higher EC50 values. The EC50 values increased with an increase in the monovalent ion (Na+) concentration in the buffer. The slope of a plot of log [EC50(Polyamine4+)] against log [Na+] was ∼1.5 for polyamin...
Zhulong Chan - One of the best experts on this subject based on the ideXlab platform.
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improvement of plant abiotic stress tolerance through modulation of the Polyamine pathway
Journal of Integrative Plant Biology, 2014Co-Authors: Haitao Shi, Zhulong ChanAbstract:Polyamines (mainly putrescine (Put), spermidine (Spd), and spermine (Spm)) have been widely found in a range of physiological processes and in almost all diverse environmental stresses. In various plant species, abiotic stresses modulated the accumulation of Polyamines and related gene expression. Studies using loss-of-function mutants and transgenic overexpression plants modulating Polyamine metabolic pathways confirmed protective roles of Polyamines during plant abiotic stress responses, and indicated the possibility to improve plant tolerance through genetic manipulation of the Polyamine pathway. Additionally, putative mechanisms of Polyamines involved in plant abiotic stress tolerance were thoroughly discussed and crosstalks among Polyamine, abscisic acid, and nitric oxide in plant responses to abiotic stress were emphasized. Special attention was paid to the interaction between Polyamine and reactive oxygen species, ion channels, amino acid and carbon metabolism, and other adaptive responses. Further studies are needed to elucidate the Polyamine signaling pathway, especially Polyamine-regulated downstream targets and the connections between Polyamines and other stress responsive molecules.
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comparative proteomic and physiological analyses reveal the protective effect of exogenous Polyamines in the bermudagrass cynodon dactylon response to salt and drought stresses
Journal of Proteome Research, 2013Co-Authors: Haitao Shi, Zhulong ChanAbstract:Polyamines conferred enhanced abiotic stress tolerance in multiple plant species. However, the effect of Polyamines on abiotic stress and physiological change in bermudagrass, the most widely used warm-season turfgrasses, are unknown. In this study, pretreatment of exogenous Polyamine conferred increased salt and drought tolerances in bermudagrass. Comparative proteomic analysis was performed to further investigate Polyamines mediated responses, and 36 commonly regulated proteins by at least two types of Polyamines in bermudagrass were successfully identified, including 12 proteins with increased level, 20 proteins with decreased level and other 4 specifically expressed proteins. Among them, proteins involved in electron transport and energy pathways were largely enriched, and nucleoside diphosphate kinase (NDPK) and three antioxidant enzymes were extensively regulated by Polyamines. Dissection of reactive oxygen species (ROS) levels indicated that Polyamine-derived H2O2 production might play dual roles u...
Anthony E Pegg - One of the best experts on this subject based on the ideXlab platform.
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Polyamine metabolism and cancer treatments challenges and opportunities
Nature Reviews Cancer, 2018Co-Authors: Robert A Casero, Tracy Murray Stewart, Anthony E PeggAbstract:Advances in our understanding of the metabolism and molecular functions of Polyamines and their alterations in cancer have led to resurgence in the interest of targeting Polyamine metabolism as an anticancer strategy. Increasing knowledge of the interplay between Polyamine metabolism and other cancer-driving pathways, including the PTEN–PI3K–mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting Polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated Polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, Polyamine blocking therapy, a strategy that combines the inhibition of Polyamine biosynthesis with the simultaneous blockade of Polyamine transport, can be more effective than therapies based on Polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant Polyamine metabolism for anticancer therapy. This Review discusses new insights into molecular mechanisms that link the dysregulation of Polyamine metabolism with carcinogenesis and strategies for targeting this pathway for cancer therapy.
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mammalian Polyamine metabolism and function
Iubmb Life, 2009Co-Authors: Anthony E PeggAbstract:Polyamines are ubiquitous small basic molecules that play multiple essential roles in mammalian physiology. Their cellular content is highly regulated and there is convincing evidence that altered metabolism is involvement in many disease states. Drugs altering Polyamine levels may therefore have a variety of important targets. This review will summarize the current state of understanding of Polyamine metabolism and function, the regulation of Polyamine content, and heritable pathological conditions that may be derived from altered Polyamine metabolism.
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Polyamines as targets for therapeutic intervention
Annual Review of Pharmacology and Toxicology, 1995Co-Authors: Laurence J Marton, Anthony E PeggAbstract:Polyamines are ubiquitous cell components essential for normal growth. Compounds interfering with Polyamine biosynthesis or function have considerable potential for use as therapeutic agents. Inhibitors of ornithine decarboxylase have been shown to be valuable for the treatment of diseases caused by parasitic protozoa, most notably African sleeping sickness. They may also be useful chemopreventive and antineoplastic agents. Inhibitors of S-adenosylmethionine decarboxylase also have potential as treatments of these diseases. Protocols minimizing uptake of exogenous Polyamines via the Polyamine-transport system will probably be needed for the full potential of the inhibitors to be realized. Polyamine analogues, notably those with ethyl or benzyl groups on the terminal nitrogen atoms, have potent antiproliferative activity and are promising agents for the treatment of cancer. These analogues are transported by the Polyamine-transport system, and their therapeutic effects are less likely to be blocked by the availability of the exogenous Polyamines.
Bonnie L Bassler - One of the best experts on this subject based on the ideXlab platform.
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inverse regulation of vibrio cholerae biofilm dispersal by Polyamine signals
eLife, 2021Co-Authors: Andrew A Bridges, Bonnie L BasslerAbstract:The global pathogen Vibrio cholerae undergoes cycles of biofilm formation and dispersal in the environment and the human host. Little is understood about biofilm dispersal. Here, we show that MbaA, a periplasmic Polyamine sensor, and PotD1, a Polyamine importer, regulate V. cholerae biofilm dispersal. Spermidine, a commonly produced Polyamine, drives V. cholerae dispersal, whereas norspermidine, an uncommon Polyamine produced by vibrios, inhibits dispersal. Spermidine and norspermidine differ by one methylene group. Both Polyamines control dispersal via MbaA detection in the periplasm and subsequent signal relay. Our results suggest that dispersal fails in the absence of PotD1 because endogenously produced norspermidine is not reimported, periplasmic norspermidine accumulates, and it stimulates MbaA signaling. These results suggest that V. cholerae uses MbaA to monitor environmental Polyamines, blends of which potentially provide information about numbers of 'self' and 'other'. This information is used to dictate whether or not to disperse from biofilms.
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inverse regulation of vibrio cholerae biofilm dispersal by Polyamine signals
bioRxiv, 2020Co-Authors: Andrew A Bridges, Bonnie L BasslerAbstract:The global pathogen Vibrio cholerae undergoes cycles of biofilm formation and dispersal in the environment and the human host. Little is understood about biofilm dispersal. Here, we show that MbaA, a periplasmic Polyamine sensor, and PotD1, a Polyamine importer, regulate V. cholerae biofilm dispersal. Spermidine, a commonly produced Polyamine, drives V. cholerae dispersal, whereas norspermidine, an uncommon Polyamine produced by vibrios, inhibits dispersal. Spermidine and norspermidine differ by one methylene group. Both Polyamines function to control dispersal via periplasmic detection by MbaA and subsequent signal relay. Biofilm dispersal fails in the absence of PotD1 because reuptake of endogenously produced norspermidine does not occur, so it accumulates in the periplasm where it stimulates MbaA. These results suggest that V. cholerae uses MbaA to monitor environmental Polyamines, blends of which potentially provide information about numbers of "self" and "other". This information is used to dictate whether or not to disperse from biofilms.
