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  1. AU="Robert A Casero Jr"
  2. AU="Marinec, Paul S"
  3. AU="Rajebhosale, Prithviraj"

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  1. 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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  2. 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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  3. Article: Arginase 2 deletion leads to enhanced M1 macrophage activation and upregulated polyamine metabolism in response to Helicobacter pylori infection

    Hardbower, Dana M / Keith T. Wilson / M. Blanca Piazuelo / Mohammad Asim / Nuruddeen D. Lewis / Robert A. Casero Jr / Rupesh Chaturvedi / Thomas Verriere / Tracy Murray-Stewart

    Amino acids. 2016 Oct., v. 48, no. 10

    2016  

    Abstract: We reported that arginase 2 (ARG2) deletion results in increased gastritis and decreased bacterial burden during Helicobacter pylori infection in mice. Our studies implicated a potential role for inducible nitric oxide (NO) synthase (NOS2), as Arg2 ⁻/⁠...

    Abstract We reported that arginase 2 (ARG2) deletion results in increased gastritis and decreased bacterial burden during Helicobacter pylori infection in mice. Our studies implicated a potential role for inducible nitric oxide (NO) synthase (NOS2), as Arg2 ⁻/⁻ mice exhibited increased NOS2 levels in gastric macrophages, and NO can kill H. pylori. We now bred Arg2 ⁻/⁻ to Nos2 ⁻/⁻ mice, and infected them with H. pylori. Compared to wild-type mice, both Arg2 ⁻/⁻ and Arg2 ⁻/⁻ ;Nos2 ⁻/⁻ mice exhibited increased gastritis and decreased colonization, the latter indicating that the effect of ARG2 deletion on bacterial burden was not mediated by NO. While Arg2 ⁻/⁻ mice demonstrated enhanced M1 macrophage activation, Nos2 ⁻/⁻ and Arg2 ⁻/⁻ ;Nos2 ⁻/⁻ mice did not demonstrate these changes, but exhibited increased CXCL1 and CXCL2 responses. There was an increased expression of the Th1/Th17 cytokines, interferon gamma and interleukin 17, in gastric tissues and splenic T-cells from Arg2 ⁻/⁻, but not Nos2 ⁻/⁻ or Arg2 ⁻/⁻ ;Nos2 ⁻/⁻ mice. Gastric tissues from infected Arg2 ⁻/⁻ mice demonstrated increased expression of arginase 1, ornithine decarboxylase, adenosylmethionine decarboxylase 1, spermidine/spermine N ¹-acetyltransferase 1, and spermine oxidase, along with increased spermine levels. These data indicate that ARG2 deletion results in compensatory upregulation of gastric polyamine synthesis and catabolism during H. pylori infection, which may contribute to increased gastric inflammation and associated decreased bacterial load. Overall, the finding of this study is that ARG2 contributes to the immune evasion of H. pylori by restricting M1 macrophage activation and polyamine metabolism.
    Keywords adenosylmethionine decarboxylase ; arginase ; chemokine CXCL1 ; chemokine CXCL2 ; gastritis ; Helicobacter pylori ; immune evasion ; inducible nitric oxide synthase ; inflammation ; interferon-gamma ; interleukin-17 ; macrophage activation ; macrophages ; metabolism ; mice ; microbial load ; nitric oxide ; ornithine decarboxylase ; spermidine ; spermine ; T-lymphocytes
    Language English
    Dates of publication 2016-10
    Size p. 2375-2388.
    Publishing place Springer Vienna
    Document type Article
    ZDB-ID 1121341-3
    ISSN 1438-2199 ; 0939-4451
    ISSN (online) 1438-2199
    ISSN 0939-4451
    DOI 10.1007/s00726-016-2231-2
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: MOF Acetylates the Histone Demethylase LSD1 to Suppress Epithelial-to-Mesenchymal Transition

    Huacheng Luo / Anitha K. Shenoy / Xuehui Li / Yue Jin / Lihua Jin / Qingsong Cai / Ming Tang / Yang Liu / Hao Chen / David Reisman / Lizi Wu / Edward Seto / Yi Qiu / Yali Dou / Robert A. Casero Jr. / Jianrong Lu

    Cell Reports, Vol 15, Iss 12, Pp 2665-

    2016  Volume 2678

    Abstract: The histone demethylase LSD1 facilitates epithelial-to-mesenchymal transition (EMT) and tumor progression by repressing epithelial marker expression. However, little is known about how its function may be modulated. Here, we report that LSD1 is ... ...

    Abstract The histone demethylase LSD1 facilitates epithelial-to-mesenchymal transition (EMT) and tumor progression by repressing epithelial marker expression. However, little is known about how its function may be modulated. Here, we report that LSD1 is acetylated in epithelial but not mesenchymal cells. Acetylation of LSD1 reduces its association with nucleosomes, thus increasing histone H3K4 methylation at its target genes and activating transcription. The MOF acetyltransferase interacts with LSD1 and is responsible for its acetylation. MOF is preferentially expressed in epithelial cells and is downregulated by EMT-inducing signals. Expression of exogenous MOF impedes LSD1 binding to epithelial gene promoters and histone demethylation, thereby suppressing EMT and tumor invasion. Conversely, MOF depletion enhances EMT and tumor metastasis. In human cancer, high MOF expression correlates with epithelial markers and a favorable prognosis. These findings provide insight into the regulation of LSD1 and EMT and identify MOF as a critical suppressor of EMT and tumor progression.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2016-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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