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  1. AU="Stewart, Tracy Murray"
  2. AU="Kong, Tsz-Ho"
  3. AU="Rennie, Sarah C"
  4. AU="Haider, Nafees"
  5. AU="Austin, Eric D"
  6. AU="Czechowicz, Agnieszka D"
  7. AU="Nume, Cosimo"
  8. AU=Cianferoni Antonella
  9. AU="Fernandez, Sarai Quirós"
  10. AU="Hajiabadi, Fatemeh"
  11. AU="Aslam, Muhammad M"
  12. AU="Wang, Xiangpei"
  13. AU="Stacey, Jemaine E"
  14. AU="Yu, Young Suk"
  15. AU=Agius R M AU=Agius R M
  16. AU="Hammer, Rachel A"
  17. AU="Dreyfuss, Jonathan M"
  18. AU="Eleanor Turner-Moss"

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  1. Artikel ; Online: Editorial to the Special Issue on "Polyamine Metabolism in Health and Disease: Potential for Polyamine-Targeted Therapies and Prevention".

    Stewart, Tracy Murray

    Medical sciences (Basel, Switzerland)

    2023  Band 11, Heft 3

    Abstract: To introduce this Special Issue, I refer the reader to the timely review by Zahedi and colleagues [ ... ]. ...

    Abstract To introduce this Special Issue, I refer the reader to the timely review by Zahedi and colleagues [...].
    Mesh-Begriff(e) Polyamines
    Chemische Substanzen Polyamines
    Sprache Englisch
    Erscheinungsdatum 2023-08-19
    Erscheinungsland Switzerland
    Dokumenttyp Editorial
    ZDB-ID 2754473-4
    ISSN 2076-3271 ; 2076-3271
    ISSN (online) 2076-3271
    ISSN 2076-3271
    DOI 10.3390/medsci11030053
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Helping the helpers: polyamines help maintain helper T-cell lineage fidelity.

    Stewart, Tracy Murray / Holbert, Cassandra E / Casero, Robert A

    Immunometabolism (Cobham (Surrey, England))

    2022  Band 4, Heft 3, Seite(n) e00002

    Abstract: The awareness that polyamines play a critical role in immune system regulation and function is coming into focus as the biological systems and analytical tools necessary to evaluate their roles have become available. Puleston et al have recently ... ...

    Abstract The awareness that polyamines play a critical role in immune system regulation and function is coming into focus as the biological systems and analytical tools necessary to evaluate their roles have become available. Puleston et al have recently demonstrated that polyamine metabolism plays a central role in helper T-cell lineage determination through the production of the translational cofactor hypusinated eIF5A and faithful epigenetic regulation through proper histone acetylation. Their findings add to the rapidly growing body of data implicating properly controlled polyamine metabolism as essential for a normally functioning immune system.
    Sprache Englisch
    Erscheinungsdatum 2022-08-05
    Erscheinungsland England
    Dokumenttyp Journal Article
    ISSN 2633-0407
    ISSN (online) 2633-0407
    DOI 10.1097/IN9.0000000000000002
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  3. Artikel ; Online: Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses.

    Chin, Alexander / Bieberich, Charles J / Stewart, Tracy Murray / Casero, Robert A

    Medical sciences (Basel, Switzerland)

    2022  Band 10, Heft 2

    Abstract: Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor ... ...

    Abstract Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and cell-extrinsic alterations within the tumor microenvironment underlying positive treatment outcomes are not well understood. Recently, investigators have demonstrated that co-targeting polyamine biosynthesis and transport alters the immune landscape. Although the polyamine synthesis-targeting drug 2-difluoromethylornithine (DFMO) is well tolerated in humans and is FDA-approved for African trypanosomiasis, its clinical benefit in treating established cancers has not yet been fully realized; however, combination therapies targeting compensatory mechanisms have shown tolerability and efficacy in animal models and are currently being tested in clinical trials. As demonstrated in pre-clinical models, polyamine blocking therapy (PBT) reduces immunosuppression in the tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, DFMO may sensitize tumors to other therapeutics, including immunotherapies and chemotherapies.
    Mesh-Begriff(e) Animals ; Cell Proliferation ; Eflornithine/pharmacology ; Eflornithine/therapeutic use ; Neoplasms/drug therapy ; Polyamines ; Tumor Microenvironment
    Chemische Substanzen Polyamines ; Eflornithine (ZQN1G5V6SR)
    Sprache Englisch
    Erscheinungsdatum 2022-06-10
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2754473-4
    ISSN 2076-3271 ; 2076-3271
    ISSN (online) 2076-3271
    ISSN 2076-3271
    DOI 10.3390/medsci10020031
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Polyamine Catabolism and Its Role in Renal Injury and Fibrosis in Mice Subjected to Repeated Low-Dose Cisplatin Treatment.

    Zahedi, Kamyar / Barone, Sharon / Brooks, Marybeth / Stewart, Tracy Murray / Foley, Jackson R / Nwafor, Ashley / Casero, Robert A / Soleimani, Manoocher

    Biomedicines

    2024  Band 12, Heft 3

    Abstract: Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of cisplatin- and vehicle-treated mice on days 3 (early injury phase) and 35 (late injury/ ...

    Abstract Cisplatin, a chemotherapeutic agent, can cause nephrotoxic and ototoxic injuries. Using a mouse model of repeated low dose cisplatin (RLDC), we compared the kidneys of cisplatin- and vehicle-treated mice on days 3 (early injury phase) and 35 (late injury/recovery phase) after the final treatment. RNA-seq analyses revealed increases in the expression of markers of kidney injury (e.g., lipocalin 2 and kidney injury molecule 1) and fibrosis (e.g., collagen 1, fibronectin, and vimentin 1) in RLDC mice. In addition, we observed increased expression of polyamine catabolic enzymes (spermidine/spermine N
    Sprache Englisch
    Erscheinungsdatum 2024-03-13
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines12030640
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Polyamines in cancer: integrating organismal metabolism and antitumour immunity.

    Holbert, Cassandra E / Cullen, Michael T / Casero, Robert A / Stewart, Tracy Murray

    Nature reviews. Cancer

    2022  Band 22, Heft 8, Seite(n) 467–480

    Abstract: The natural mammalian polyamines putrescine, spermidine and spermine are essential for both normal and neoplastic cell function and replication. Dysregulation of metabolism of polyamines and their requirements is common in many cancers. Both clinical and ...

    Abstract The natural mammalian polyamines putrescine, spermidine and spermine are essential for both normal and neoplastic cell function and replication. Dysregulation of metabolism of polyamines and their requirements is common in many cancers. Both clinical and experimental depletion of polyamines have demonstrated their metabolism to be a rational target for therapy; however, the mechanisms through which polyamines can establish a tumour-permissive microenvironment are only now emerging. Recent data indicate that polyamines can play a major role in regulating the antitumour immune response, thus likely contributing to the existence of immunologically 'cold' tumours that do not respond to immune checkpoint blockade. Additionally, the interplay between the microbiota and associated tissues creates a tumour microenvironment in which polyamine metabolism, content and function can all be dramatically altered on the basis of microbiota composition, dietary polyamine availability and tissue response to its surrounding microenvironment. The goal of this Perspective is to introduce the reader to the many ways in which polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be successfully targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.
    Mesh-Begriff(e) Animals ; Humans ; Mammals/metabolism ; Neoplasms ; Polyamines/metabolism ; Putrescine ; Spermidine ; Spermine ; Tumor Microenvironment
    Chemische Substanzen Polyamines ; Spermine (2FZ7Y3VOQX) ; Spermidine (U87FK77H25) ; Putrescine (V10TVZ52E4)
    Sprache Englisch
    Erscheinungsdatum 2022-04-27
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2062767-1
    ISSN 1474-1768 ; 1474-175X
    ISSN (online) 1474-1768
    ISSN 1474-175X
    DOI 10.1038/s41568-022-00473-2
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Reduction of spermine synthase enhances autophagy to suppress Tau accumulation.

    Tao, Xianzun / Liu, Jiaqi / Diaz-Perez, Zoraida / Foley, Jackson R / Nwafor, Ashley / Stewart, Tracy Murray / Casero, Robert A / Zhai, R Grace

    Cell death & disease

    2024  Band 15, Heft 5, Seite(n) 333

    Abstract: Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder-Robinson intellectual disability syndrome (SRS), characterized by significant spermidine accumulation and autophagy blockage in ... ...

    Abstract Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder-Robinson intellectual disability syndrome (SRS), characterized by significant spermidine accumulation and autophagy blockage in the nervous system. Emerging evidence connects polyamine metabolism with other autophagy-related diseases, such as Tauopathy, however, the functional intersection between polyamine metabolism and autophagy in the context of these diseases remains unclear. Here, we altered SMS expression level to investigate the regulation of autophagy by modulated polyamine metabolism in Tauopathy in Drosophila and human cellular models. Interestingly, while complete loss of Drosophila spermine synthase (dSms) impairs lysosomal function and blocks autophagic flux recapitulating SRS disease phenotype, partial loss of dSms enhanced autophagic flux, reduced Tau protein accumulation, and led to extended lifespan and improved climbing performance in Tauopathy flies. Measurement of polyamine levels detected a mild elevation of spermidine in flies with partial loss of dSms. Similarly, in human neuronal or glial cells, partial loss of SMS by siRNA-mediated knockdown upregulated autophagic flux and reduced Tau protein accumulation. Importantly, proteomics analysis of postmortem brain tissue from Alzheimer's disease (AD) patients showed a significant albeit modest elevation of SMS level. Taken together, our study uncovers a functional correlation between polyamine metabolism and autophagy in AD: SMS reduction upregulates autophagy, suppresses Tau accumulation, and ameliorates neurodegeneration and cell death. These findings provide a new potential therapeutic target for AD.
    Mesh-Begriff(e) Autophagy ; Animals ; tau Proteins/metabolism ; Humans ; Spermine Synthase/metabolism ; Spermine Synthase/genetics ; Drosophila melanogaster/metabolism ; Drosophila Proteins/metabolism ; Drosophila Proteins/genetics ; Tauopathies/metabolism ; Tauopathies/pathology ; Neurons/metabolism ; Neurons/pathology ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Alzheimer Disease/genetics ; Spermidine/metabolism ; Disease Models, Animal ; Lysosomes/metabolism ; Drosophila/metabolism ; Mental Retardation, X-Linked
    Chemische Substanzen tau Proteins ; Spermine Synthase (EC 2.5.1.22) ; Drosophila Proteins ; Spermidine (U87FK77H25)
    Sprache Englisch
    Erscheinungsdatum 2024-05-13
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-024-06720-8
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel: Polyamine transport inhibition and cisplatin synergistically enhance tumor control through oxidative stress in murine head and neck cancer models.

    Yassin-Kassab, Abdulkader / Wang, Nathaniel / Foley, Jackson / Stewart, Tracy Murray / Burns, Mark R / Casero, Robert A / Harbison, R Alex / Duvvuri, Umamaheswar

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Background: Surgery and/or platinum-based chemoradiation remain standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While these therapies are effective in a subset of patients, a substantial proportion experience recurrence ...

    Abstract Background: Surgery and/or platinum-based chemoradiation remain standard of care for patients with head and neck squamous cell carcinoma (HNSCC). While these therapies are effective in a subset of patients, a substantial proportion experience recurrence or treatment resistance. As cisplatin mediates cytotoxicity through oxidative stress while polyamines play a role in redox regulation, we posited that combining cisplatin with polyamine transport inhibitor, AMXT-1501, would increase oxidative stress and tumor cell death in HNSCC cells.
    Methods: Cell proliferation was measured in syngeneic mouse HNSCC cell lines treated with cisplatin ± AMXT-1501. Synergy was determined by administering cisplatin and AMXT-1501 at a ratio of 1:10 to cancer cells
    Results: The combination of cisplatin and AMXT-1501 synergize
    Conclusion: AMXT-1501 enhances the cytotoxic effects of cisplatin
    Sprache Englisch
    Erscheinungsdatum 2023-07-27
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.07.25.550524
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel: Reduction of Spermine Synthase Suppresses Tau Accumulation Through Autophagy Modulation in Tauopathy.

    Tao, Xianzun / Liu, Jiaqi / Diaz-Perez, Zoraida / Foley, Jackson R / Stewart, Tracy Murray / Casero, Robert A / Zhai, R Grace

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Tauopathy, including Alzheimer Disease (AD), is characterized by Tau protein accumulation and autophagy dysregulation. Emerging evidence connects polyamine metabolism with the autophagy pathway, however the role of polyamines in Tauopathy remains unclear. ...

    Abstract Tauopathy, including Alzheimer Disease (AD), is characterized by Tau protein accumulation and autophagy dysregulation. Emerging evidence connects polyamine metabolism with the autophagy pathway, however the role of polyamines in Tauopathy remains unclear. In the present study we investigated the role of spermine synthase (SMS) in autophagy regulation and tau protein processing in
    Sprache Englisch
    Erscheinungsdatum 2023-03-18
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.03.17.533015
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: Histone deacetylase-10 liberates spermidine to support polyamine homeostasis and tumor cell growth.

    Stewart, Tracy Murray / Foley, Jackson R / Holbert, Cassandra E / Klinke, Glynis / Poschet, Gernot / Steimbach, Raphael R / Miller, Aubry K / Casero, Robert A

    The Journal of biological chemistry

    2022  Band 298, Heft 10, Seite(n) 102407

    Abstract: Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine ... ...

    Abstract Cytosolic histone deacetylase-10 (HDAC10) specifically deacetylates the modified polyamine N
    Mesh-Begriff(e) Humans ; Cell Proliferation ; Eflornithine/pharmacology ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Homeostasis ; Neoplasms/metabolism ; Neoplasms/pathology ; Spermidine/antagonists & inhibitors ; Spermidine/metabolism ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology
    Chemische Substanzen Eflornithine (ZQN1G5V6SR) ; HDAC10 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98) ; Spermidine (U87FK77H25) ; Histone Deacetylase Inhibitors
    Sprache Englisch
    Erscheinungsdatum 2022-08-19
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.102407
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome.

    Stewart, Tracy Murray / Foley, Jackson R / Holbert, Cassandra E / Khomutov, Maxim / Rastkari, Noushin / Tao, Xianzun / Khomutov, Alex R / Zhai, R Grace / Casero, Robert A

    EMBO molecular medicine

    2023  Band 15, Heft 11, Seite(n) e17833

    Abstract: Snyder-Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and ...

    Abstract Snyder-Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2-difluoromethylornithine (DFMO), an FDA-approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential.
    Mesh-Begriff(e) Male ; Humans ; Polyamines/metabolism ; Spermidine/metabolism ; Spermidine/pharmacology ; Spermine/metabolism ; Eflornithine/pharmacology ; Eflornithine/therapeutic use ; Spermine Synthase/genetics ; Spermine Synthase/metabolism
    Chemische Substanzen Polyamines ; Spermidine (U87FK77H25) ; Spermine (2FZ7Y3VOQX) ; Eflornithine (ZQN1G5V6SR) ; Spermine Synthase (EC 2.5.1.22)
    Sprache Englisch
    Erscheinungsdatum 2023-09-13
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.15252/emmm.202317833
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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