bims-polyam 2021-12-26 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2021–12–26
seven papers selected by
Sebastian J. Hofer, University of Graz

Spermidine Affects Cardiac Function in Heart Failure Mice by Influencing the Gut Microbiota and Cardiac Galectin-3.
Responses of Polyamine-Metabolic Genes to Polyamines and Plant Stress Hormones in Arabidopsis Seedlings.
Differential Expression of Polyamine Pathways in Human Pancreatic Tumor Progression and Effects of Polyamine Blockade on Tumor Microenvironment.
Systemic L-ornithine supplementation specifically increases ovarian putrescine levels during ovulation in mice.
Overexpression and biochemical characterization of a carboxyspermidine dehydrogenase from Agrobacterium fabrum str. C58 and its application on carboxyspermidine production.
DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment.
eIF5A-Independent Role of DHPS in p21CIP1 and Cell Fate Regulation.

Front Cardiovasc Med. 2021 ;8 765591

Spermidine Affects Cardiac Function in Heart Failure Mice by Influencing the Gut Microbiota and Cardiac Galectin-3.

Yufeng Chen, Zhiqin Guo, Shaonan Li, Zhen Liu, Pingan Chen.

  Spermidine, which can be synthesized by the gut microbiota, can prevent cardiac hypertrophy and delay the progression to heart failure (HF). However, it is not clear whether the effect of spermidine on cardiac function is mediated by modulating the gut microbiota when HF occurs. Female HF Kunming mice induced by transverse aortic constriction were administered spermidine (HF+S group) or its antagonist (HF+SR group). Echocardiography, messenger ribonucleic acid (RNA) and protein expression of galectin-3 in the heart, cardiomyocyte apoptosis assays and gut microbiota analysis were detected. Left ventricular end-diastolic volume and diameter (LVVd and LVDd), and left ventricular end-systolic volume and diameter in the HF+SR group were significantly enlarged compared with those in the HF group (all P < 0.05). The HF+S group had a smaller LVDd and LVVd than the HF+SR group (5.01 ± 0.67 vs. 6.13 ± 0.45 mm, P = 0.033; 121.44 ± 38.74 vs. 189.94 ± 31.42 μL, P = 0.033). The messenger RNA and protein expression of galectin-3 and the number of apoptotic cardiomyocytes increased significantly in the HF+SR group compared to the HF group. Gut microbiota analysis showed that spermidine antagonists reduced the Firmicutes/Bacteroidetes ratio and changed the microbial community richness and diversity. In conclusion, spermidine can improve cardiac function in HF, and the regulation of gut microbiota and cardiac fibrosis may be a factor in the effect of spermidine on the improvement of cardiac function.

Keywords:  cardiac fibrosis; galectin-3; heart failure; microbiota; spermidine

DOI:  https://doi.org/10.3389/fcvm.2021.765591
Cells. 2021 Nov 24. pii: 3283. [Epub ahead of print]10(12):

Responses of Polyamine-Metabolic Genes to Polyamines and Plant Stress Hormones in Arabidopsis Seedlings.

Yusaku Yariuchi, Takashi Okamoto, Yoshiteru Noutoshi, Taku Takahashi.

  In plants, many of the enzymes in polyamine metabolism are encoded by multiple genes, whose expressions are differentially regulated under different physiological conditions. For comprehensive understanding of their regulation during the seedling growth stage, we examined the expression of polyamine metabolic genes in response to polyamines and stress-related plant hormones in Arabidopsis thaliana. While confirming previous findings such as induction of many of the genes by abscisic acid, induction of arginase genes and a copper amine oxidase gene, CuAOα3, by methyl jasmonate, that of an arginine decarboxylase gene, ADC2, and a spermine synthase gene, SPMS, by salicylic acid, and negative feedback regulation of thermospermine biosynthetic genes by thermospermine, our results showed that expressions of most of the genes are not responsive to exogenous polyamines. We thus examined expression of OsPAO6, which encodes an apoplastic polyamine oxidase and is strongly induced by polyamines in rice, by using the promoter-GUS fusion in transgenic Arabidopsis seedlings. The GUS activity was increased by treatment with methyl jasmonate but neither by polyamines nor by other plant hormones, suggesting a difference in the response to polyamines between Arabidopsis and rice. Our results provide a framework to study regulatory modules directing expression of each polyamine metabolic gene.

Keywords:  Arabidopsis; abscisic acid; jasmonate; polyamine metabolism; salicylic acid

DOI:  https://doi.org/10.3390/cells10123283
Cancers (Basel). 2021 Dec 20. pii: 6391. [Epub ahead of print]13(24):

Differential Expression of Polyamine Pathways in Human Pancreatic Tumor Progression and Effects of Polyamine Blockade on Tumor Microenvironment.

Sai Preethi Nakkina, Sarah B Gitto, Veethika Pandey, Jignesh G Parikh, Dirk Geerts, Hans Carlo Maurer, Kenneth P Olive, Otto Phanstiel, Deborah A Altomare.

  Pancreatic cancer is the fourth leading cause of cancer death. Existing therapies only moderately improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The present study investigates the importance of the polyamine metabolism in the pancreatic tumor microenvironment. Relative mRNA expression analysis identified differential expression of polyamine biosynthesis, homeostasis, and transport mediators in both pancreatic epithelial and stromal cells from low-grade pancreatic intraepithelial neoplasia (PanIN-1) or primary PDAC patient samples. We found dysregulated mRNA levels that encode for proteins associated with the polyamine pathway of PDAC tumors compared to early lesions. Next, bioinformatic databases were used to assess expression of select genes involved in polyamine metabolism and their impact on patient survival. Higher expression of pro-polyamine genes was associated with poor patient prognosis, supporting the use of a polyamine blockade therapy (PBT) strategy for inhibiting pancreatic tumor progression. Moreover, PBT treatment of syngeneic mice injected intra-pancreatic with PAN 02 tumor cells resulted in increased survival and decreased tumor weights of PDAC-bearing mice. Histological assessment of PBT-treated tumors revealed macrophage presence and significantly increased expression of CD86, a T cell co-stimulatory marker. Collectively, therapies which target polyamine metabolism can be used to disrupt tumor progression, modulate tumor microenvironment, and extend overall survival.

Keywords:  CD86; DFMO; immune suppression; macrophage; pancreatic ductal adenocarcinoma; polyamine blockade therapy; polyamine metabolism; polyamine transport inhibitor; survival; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13246391
Biol Reprod. 2021 Dec 22. pii: ioab233. [Epub ahead of print]

Systemic L-ornithine supplementation specifically increases ovarian putrescine levels during ovulation in mice.

Christopher L J Lavergne, Yong Tao, Yanping Ren, Nahantara Lafleur, X Johné Liu.

  In all mammalian species examined thus far, the ovaries produce a burst of ornithine decarboxylase (ODC) and putrescine during ovulation or after application of human chorionic gonadotropin (hCG). Aged mice have significantly reduced levels of this periovulatory ODC and putrescine rise. Putrescine supplementation, in vitro during oocyte maturation or in mouse drinking water during the periovulatory period, reduces egg aneuploidies and embryo resorption, improving fertility of aged mice. These studies suggest that periovulatory putrescine supplementation may be a simple and effective therapy for reproductive aging for women. However, putrescine supplementation is expected to increase widespread tissue putrescine levels, raising concerns of nonspecific and unwanted side effects. Given that ODC is highly expressed in the ovaries during ovulation but otherwise exhibits low activity in most tissues, we hypothesized that periovulatory supplementation of L-ornithine, the substrate of ODC, might be suitable for delivering putrescine specifically to the ovaries. In this study, we have demonstrated that systemic application of L-ornithine via oral gavage or subcutaneous injection increased ovarian putrescine levels; the increase was restricted to animals that had been injected with hCG. Furthermore, L-ornithine specifically increased ovarian putrescine levels without affecting putrescine levels in any other tissues. However, our attempts to improve fertility of aged mice through L-ornithine supplementation in mouse drinking water produced either no effects (1% L-ornithine) or negative impact on fertility (4% ornithine). Our results suggest that it might not be feasible to achieve fertility-enhancing ovarian putrescine levels via L-ornithine supplementation in drinking water without encountering undesired consequences of high dose of exogenous L-ornithine.

Keywords:  Infertility; L-ornithine; aging; ornithine decarboxylase; ovaries; putrescine

DOI:  https://doi.org/10.1093/biolre/ioab233
J Sci Food Agric. 2021 Dec 21.

Overexpression and biochemical characterization of a carboxyspermidine dehydrogenase from Agrobacterium fabrum str. C58 and its application on carboxyspermidine production.

Xinxin Liang, Huaxiang Deng, Tianzhen Xiong, Yajun Bai, Tai-Ping Fan, Xiaohui Zheng, Yujie Cai.

   BACKGROUND: Carboxyspermidine (C-Spd) is a potentially valuable polyamine carboxylate compound and an excellent building block for spermidine synthesis, which is a critical polyamine with significant implications for human health and longevity. C-Spd can also be used to prepare multivalent cationic lipids, and modify nucleoside probes. Due to these positive effects on human health, C-Spd is of considerable interest as a food additive and pharmaceutical target.
RESULTS: A putative gene afcasdh from Agrobacterium fabrum str. C58, encoding carboxyspermidine dehydrogenase with C-Spd biosynthesis activity, was synthesized and transformed into Escherichia coli BL21 (DE3) for overexpression. The recombinant AfCASDH was purified and fully characterized. The optimum temperature and pH for the recombinant enzyme were 30°C and 7.5, respectively. The coupled catalytic strategy of AfCASDH and various NADPH regeneration systems were developed to enhance the efficient production of C-Spd compound. Finally, the maximum titer of C-Spd production successfully achieved 1.82 mM with a yield of 91% by optimizing the catalytic conditions.
CONCLUSIONS: A novel AfCASDH from A. fabrum str. C58 was characterized that could catalyze the formation of C-Spd from putrescine and L-aspartate-β-semialdehyde (L-Asa). A whole-cell catalytic strategy coupled with NADPH regeneration was established successfully for C-Spd biosynthesis for the first time. The coupled system indicated that AfCASDH might provide a feasible way for the industrial production of C-Spd. This article is protected by copyright. All rights reserved.

Keywords:  carboxyspermidine; carboxyspermidine dehydrogenase; characterization; cofactor regeneration; whole-cell catalytic system

DOI:  https://doi.org/10.1002/jsfa.11735
Int J Mol Sci. 2021 Dec 07. pii: 13175. [Epub ahead of print]22(24):

DFMO Improves Survival and Increases Immune Cell Infiltration in Association with MYC Downregulation in the Pancreatic Tumor Microenvironment.

Sai Preethi Nakkina, Sarah B Gitto, Jordan M Beardsley, Veethika Pandey, Michael W Rohr, Jignesh G Parikh, Otto Phanstiel, Deborah A Altomare.

  Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor five-year survival rate of less than 10%. Immune suppression along with chemoresistance are obstacles for PDAC therapeutic treatment. Innate immune cells, such as tumor-associated macrophages, are recruited to the inflammatory environment of PDAC and adversely suppress cytotoxic T lymphocytes. KRAS and MYC are important oncogenes associated with immune suppression and pose a challenge to successful therapies. Here, we targeted KRAS, through inhibition of downstream c-RAF with GW5074, and MYC expression via difluoromethylornithine (DFMO). DFMO alone and with GW5074 reduced in vitro PDAC cell viability. Both DFMO and GW5074 showed efficacy in reducing in vivo PDAC growth in an immunocompromised model. Results in immunocompetent syngeneic tumor-bearing mice showed that DFMO and combination treatment markedly decreased tumor size, but only DFMO increased survival in mice. To further investigate, immunohistochemical staining showed DFMO diminished MYC expression and increased tumor infiltration of macrophages, CD86+ cells, CD4+ and CD8+ T lymphocytes. GW5074 was not as effective in modulating the tumor infiltration of total CD3+ lymphocytes or tumor progression and maintained MYC expression. Collectively, this study highlights that in contrast to GW5074, the inhibition of MYC through DFMO may be an effective treatment modality to modulate PDAC immunosuppression.

Keywords:  DFMO; GW5074; KRAS; MYC; c-RAF; immune suppression; pancreatic ductal adenocarcinoma; polyamine metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms222413175
Int J Mol Sci. 2021 Dec 07. pii: 13187. [Epub ahead of print]22(24):

eIF5A-Independent Role of DHPS in p21CIP1 and Cell Fate Regulation.

Andrew E Becker, Pui-Kei Wu, Jong-In Park.

  Deoxyhypusine synthase (DHPS) catalyzes the first step of hypusination of the elongation translation factor 5A (eIF5A), and these two proteins have an exclusive enzyme-substrate relationship. Here we demonstrate that DHPS has a role independent of eIF5A hypusination in A375 and SK-MEL-28 human melanoma cells, in which the extracellular signal regulated kinase 1/2 (ERK1/2) pathway is deregulated. We found that RNA interference of DHPS induces G0/G1 cell cycle arrest in association with increased p21CIP1 expression in these cells whereas eIF5A knockdown induces cell death without increasing p21CIP1 expression. Interestingly, p21CIP1 knockdown switched DHPS knockdown-induced growth arrest to cell death in these cells, suggesting a specific relation between DHPS and p21CIP1 in determining cell fate. Surprisingly, ectopic expression of DHPS-K329R mutant that cannot hypusinate eIF5A abrogated DHPS knockdown-induced p21CIP1 expression in these cells, suggesting a non-canonical role of DHPS underlying the contrasting effects of DHPS and eIF5A knockdowns. We also show that DHPS knockdown induces p21CIP1 expression in these cells by increasing CDKN1A transcription through TP53 and SP1 in an ERK1/2-dependent manner. These data suggest that DHPS has a role independent of its ability to hypusinate eIF5A in cells, which appears to be important for regulating p21CIP1 expression and cell fate.

Keywords:  BRAF; ERK1/2; cell death; deoxyhypusine synthase; eukaryotic initiation factor 5A; growth arrest; p21CIP1

DOI:  https://doi.org/10.3390/ijms222413187