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Article: 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 Volume 12, Issue 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
Language	English
Publishing date	2024-03-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines12030640
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Article ; Online: Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder–Robinson syndrome

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

EMBO Molecular Medicine, Vol 15, Iss 11, Pp n/a-n/a (2023)

2023

Abstract: 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, ... ...

Abstract	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.
Keywords	alpha‐methylated polyamine analogue ; eflornithine ; S‐adenosylmethionine decarboxylase ; spermidine ; spermine synthase ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Subject code	572
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Expanded Potential of the Polyamine Analogue SBP-101 (Diethyl Dihydroxyhomospermine) as a Modulator of Polyamine Metabolism and Cancer Therapeutic.

Holbert, Cassandra E / Foley, Jackson R / Murray Stewart, Tracy / Casero, Robert A

International journal of molecular sciences

2022 Volume 23, Issue 12

Abstract: Naturally occurring polyamines are absolutely required for cellular growth and proliferation. Many neoplastic cells are reliant on elevated polyamine levels and maintain these levels through dysregulated polyamine metabolism. The modulation of polyamine ... ...

Abstract	Naturally occurring polyamines are absolutely required for cellular growth and proliferation. Many neoplastic cells are reliant on elevated polyamine levels and maintain these levels through dysregulated polyamine metabolism. The modulation of polyamine metabolism is thus a promising avenue for cancer therapeutics and has been attempted with numerous molecules, including enzyme inhibitors and polyamine analogues. SBP-101 (diethyl dihydroxyhomospermine) is a spermine analogue that has shown efficacy in slowing pancreatic tumor progression both in vitro and in vivo; however, the mechanisms underlying these effects remain unclear. We determined the effects of the SBP-101 treatment on a variety of cancer cell types in vitro, including lung, pancreatic, and ovarian. We evaluated the activity of enzymes involved in polyamine metabolism and the effect on intracellular polyamine pools following the SBP-101 treatment. The SBP-101 treatment produced a modest but variable increase in polyamine catabolism; however, a robust downregulation of the activity of the biosynthetic enzyme, ornithine decarboxylase (ODC), was seen across all of the cell types studied and indicates that SBP-101 likely exerts its effect predominately through the downregulation of ODC, with a minor upregulation of catabolism. Our in vitro work indicated that SBP-101 was most toxic in the tested ovarian cell lines. Therefore, we evaluated the efficacy of SBP-101 as a monotherapy in the immunosuppressive VDID8
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Mice ; Neoplasms/drug therapy ; Ornithine Decarboxylase/metabolism ; Polyamines/metabolism ; Spermine/metabolism
Chemical Substances	Antineoplastic Agents ; Polyamines ; Spermine (2FZ7Y3VOQX) ; Ornithine Decarboxylase (EC 4.1.1.17)
Language	English
Publishing date	2022-06-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23126798
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Article ; Online: Elucidating the Role of

Stump, Coryn L / Casero, Robert A / Phanstiel, Otto / DiAngelo, Justin R / Nowotarski, Shannon L

Medical sciences (Basel, Switzerland)

2022 Volume 10, Issue 3

Abstract: Polyamines are small organic cations that are essential for many biological processes such as cell proliferation and cell cycle progression. While the metabolism of polyamines has been well studied, the mechanisms by which polyamines are transported into ...

Abstract	Polyamines are small organic cations that are essential for many biological processes such as cell proliferation and cell cycle progression. While the metabolism of polyamines has been well studied, the mechanisms by which polyamines are transported into and out of cells are poorly understood. Here, we describe a novel role of Chmp1, a vesicular trafficking protein, in the transport of polyamines using a well-defined leg imaginal disc assay in
MeSH term(s)	Animals ; Drosophila melanogaster/metabolism ; Eflornithine/pharmacology ; Polyamines/metabolism ; Polyamines/pharmacology ; Putrescine/metabolism ; Putrescine/pharmacology ; Spermidine/metabolism ; Spermidine/pharmacology ; Spermine/metabolism ; Spermine/pharmacology
Chemical Substances	Polyamines ; Spermine (2FZ7Y3VOQX) ; Spermidine (U87FK77H25) ; Putrescine (V10TVZ52E4) ; Eflornithine (ZQN1G5V6SR)
Language	English
Publishing date	2022-08-25
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2754473-4
ISSN	2076-3271 ; 2076-3271
ISSN (online)	2076-3271
ISSN	2076-3271
DOI	10.3390/medsci10030045
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Article: 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
Language	English
Publishing date	2023-03-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.17.533015
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Article ; Online: Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson Syndrome.

Akinyele, Oluwaseun / Munir, Anushe / Johnson, Marie A / Perez, Megan S / Gao, Yuan / Foley, Jackson R / Nwafor, Ashley / Wu, Yijen / Murray-Stewart, Tracy / Casero, Robert A / Bayir, Hulya / Kemaladewi, Dwi U

Disease models & mechanisms

2024

Abstract: Snyder-Robinson Syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene encoding spermine synthase and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle ... ...

Abstract	Snyder-Robinson Syndrome (SRS) is a rare X-linked recessive disorder caused by a mutation in the SMS gene encoding spermine synthase and aberrant polyamine metabolism. SRS is characterized by intellectual disability, thin habitus, seizure, low muscle tone/hypotonia, and osteoporosis. Progress towards understanding and treating SRS requires a model that recapitulates human mutations and disease presentations. Here, we evaluated molecular and neurological presentations in the G56S mouse model carrying a missense mutation in the Sms gene. The lack of SMS protein in the G56S mice resulted in increased spermidine/spermine ratio, failure to thrive, short stature, and reduced bone density. They showed impaired learning capacity, increased anxiety, reduced mobility, and heightened fear responses, accompanied by reduced total and regional brain volumes. Furthermore, impaired mitochondrial oxidative phosphorylation was evident in G56S cerebral cortex, G56S fibroblasts, and Sms-null hippocampal cells, and may serve as a future therapeutic target. Collectively, our study establishes the suitability of the G56S mice as a preclinical model for SRS and provides a set of molecular and functional outcome measures that can be used to evaluate therapeutic interventions for SRS.
Language	English
Publishing date	2024-03-11
Publishing country	England
Document type	Journal Article
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.050639
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Article ; Online: Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells

Xianzun Tao / Yi Zhu / Zoraida Diaz-Perez / Seok-Ho Yu / Jackson R. Foley / Tracy Murray Stewart / Robert A. Casero Jr. / Richard Steet / R. Grace Zhai

JCI Insight, Vol 7, Iss

2022 Volume 13

Abstract: Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic disorder of the polyamine pathway, caused by X-linked recessive loss-of-function ... ...

Abstract	Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic disorder of the polyamine pathway, caused by X-linked recessive loss-of-function mutations in spermine synthase. In the Drosophila SRS model, altered spermidine/spermine balance has been associated with increased generation of ROS and aldehydes, consistent with elevated spermidine catabolism. These toxic byproducts cause mitochondrial and lysosomal dysfunction, which are also observed in cells from SRS patients. No efficient therapy is available. We explored the biochemical mechanism and discovered acetyl-CoA reduction and altered protein acetylation as potentially novel pathomechanisms of SRS. We repurposed the FDA-approved drug phenylbutyrate (PBA) to treat SRS using an in vivo Drosophila model and patient fibroblast cell models. PBA treatment significantly restored the function of mitochondria and autolysosomes and extended life span in vivo in the Drosophila SRS model. Treating fibroblasts of patients with SRS with PBA ameliorated autolysosome dysfunction. We further explored the mechanism of drug action and found that PBA downregulates the first and rate-limiting spermidine catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), reduces the production of toxic metabolites, and inhibits the reduction of the substrate acetyl-CoA. Taken together, we revealed PBA as a potential modulator of SAT1 and acetyl-CoA levels and propose PBA as a therapy for SRS and potentially other polyamine dysregulation–related diseases.
Keywords	Genetics ; Therapeutics ; Medicine ; R
Subject code	572
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy.

Holbert, Cassandra E / Foley, Jackson R / Yu, Ao / Murray Stewart, Tracy / Phanstiel, Otto / Oupicky, David / Casero, Robert A

Medical sciences (Basel, Switzerland)

2022 Volume 10, Issue 3

Abstract: Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including cell proliferation, survival, and protection from oxidative stress. Polyamine homeostasis is tightly regulated through coordinated biosynthesis, ... ...

Abstract	Polyamines are small polycationic alkylamines involved in many fundamental cellular processes, including cell proliferation, survival, and protection from oxidative stress. Polyamine homeostasis is tightly regulated through coordinated biosynthesis, catabolism, and transport. Due to their continual proliferation, cancer cells maintain elevated intracellular polyamine pools. Both polyamine metabolism and transport are commonly dysregulated in cancer, and as such, polyamine analogues are a promising strategy for exploiting the increased polyamine requirement of cancer cells. One potential polyamine analogue resistance mechanism is the downregulation of the poorly defined polyamine transport system. Recent advances in nanomedicine have produced nanostructures with polyamine analogue-based backbones (nanopolyamines). Similar nanostructures with non-polyamine backbones have been shown to be transported by endocytosis. As these polyamine-based nanoparticles could be a method for polyamine analogue delivery that bypasses polyamine transport, we designed the current studies to determine the efficacy of polyamine-based nanoparticles in cells lacking intact polyamine transport. Utilizing polyamine transport-deficient derivatives of lung adenocarcinoma lines, we demonstrated that cells unable to transport natural polyamines were also resistant to nanopolyamine-induced cytotoxicity. This resistance was a result of transport-deficient cells being incapable of importing and accumulating nanopolyamines. Pharmacological modulation of polyamine transport confirmed these results in polyamine transport competent cells. These studies provide additional insight into the polyamine transport pathway and suggest that receptor-mediated endocytosis is a likely mechanism of transport for higher-order polyamines, polyamine analogues and the nanopolyamines.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Humans ; Nanomedicine ; Nanostructures ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Polyamines/chemistry ; Polyamines/metabolism ; Polyamines/pharmacology
Chemical Substances	Antineoplastic Agents ; Polyamines
Language	English
Publishing date	2022-08-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2754473-4
ISSN	2076-3271 ; 2076-3271
ISSN (online)	2076-3271
ISSN	2076-3271
DOI	10.3390/medsci10030044
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Article ; 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 Volume 298, Issue 10, Page(s) 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 term(s)	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
Chemical Substances	Eflornithine (ZQN1G5V6SR) ; HDAC10 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98) ; Spermidine (U87FK77H25) ; Histone Deacetylase Inhibitors
Language	English
Publishing date	2022-08-19
Publishing country	United States
Document type	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
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Article: Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a novel mouse model of Snyder-Robinson Syndrome.

Akinyele, Oluwaseun / Munir, Anushe / Johnson, Marie A / Perez, Megan S / Gao, Yuan / Foley, Jackson R / Wu, Yijen / Murray-Stewart, Tracy / Casero, Robert A / Bayir, Hulya / Kemaladewi, Dwi U

bioRxiv : the preprint server for biology

2023

Abstract: Polyamines (putrescine, spermidine, and spermine) are essential molecules for normal cellular functions and are subject to strict metabolic regulation. Mutations in the gene encoding spermine synthase (SMS) lead to accumulation of spermidine in an X- ... ...

Abstract	Polyamines (putrescine, spermidine, and spermine) are essential molecules for normal cellular functions and are subject to strict metabolic regulation. Mutations in the gene encoding spermine synthase (SMS) lead to accumulation of spermidine in an X-linked recessive disorder known as Snyder-Robinson syndrome (SRS). Presently, no treatments exist for this rare disease that manifests with a spectrum of symptoms including intellectual disability, developmental delay, thin habitus, and low muscle tone. The development of therapeutic interventions for SRS will require a suitable disease-specific animal model that recapitulates many of the abnormalities observed in patients. Here, we characterize the molecular, behavioral, and neuroanatomical features of a mouse model with a missense mutation in
Language	English
Publishing date	2023-02-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.15.524155
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