bims-polyam 2023-07-16 papers

bims-polyam

Biomed News

on Polyamines

Issue of 2023‒07‒16
five papers selected by
Sebastian J. Hofer
University of Graz

Molecular targets of spermidine: implications for cancer suppression.
Kinetic and structural characterization of carboxyspermidine dehydrogenase of polyamine biosynthesis.
BRG1 mediates protective ability of spermidine to ameliorate osteoarthritic cartilage by Nrf2/KEAP1 and STAT3 signaling pathway.
Spermidine alleviating oxidative stress and apoptosis by inducing autophagy of granulosa cells in Sichuan white geese.
Spermidine Attenuates High Glucose-Induced Oxidative Damage in Retinal Pigment Epithelial Cells by Inhibiting Production of ROS and NF-κB/NLRP3 Inflammasome Pathway.

Cell Stress. 2023 Jul;7(7): 50-58

Molecular targets of spermidine: implications for cancer suppression.

Andreas Zimmermann, Sebastian J Hofer, Frank Madeo.

  Spermidine is a ubiquitous, natural polyamine with geroprotective features. Supplementation of spermidine extends the lifespan of yeast, worms, flies, and mice, and dietary spermidine intake correlates with reduced human mortality. However, the crucial role of polyamines in cell proliferation has also implicated polyamine metabolism in neoplastic diseases, such as cancer. While depleting intracellular polyamine biosynthesis halts tumor growth in mouse models, lifelong external spermidine administration in mice does not increase cancer incidence. In contrast, a series of recent findings points to anti-neoplastic properties of spermidine administration in the context of immunotherapy. Various molecular mechanisms for the anti-aging and anti-cancer properties have been proposed, including the promotion of autophagy, enhanced translational control, and augmented mitochondrial function. For instance, spermidine allosterically activates mitochondrial trifunctional protein (MTP), a bipartite protein complex that mediates three of the four steps of mitochondrial fatty acid (β-oxidation. Through this action, spermidine supplementation is able to restore MTP-mediated mitochondrial respiratory capacity in naïve CD8+ T cells to juvenile levels and thereby improves T cell activation in aged mice. Here, we put this finding into the context of the previously described molecular target space of spermidine.

Keywords:  autophagy; cancer; hypusination; immunosurveillance; molecular targets; spermidine

DOI:  https://doi.org/10.15698/cst2023.07.281
J Biol Chem. 2023 Jul 10. pii: S0021-9258(23)02061-6. [Epub ahead of print] 105033

Kinetic and structural characterization of carboxyspermidine dehydrogenase of polyamine biosynthesis.

Danielle F Lee, Nicole Atencio, Shade Bouchey, Madeline R Shoemaker, Joshua S Dodd, Meredith Satre, Kenneth A Miller, Jeffrey S McFarlane.

  Polyamines are positively charged alkylamines ubiquitous among eukaryotes, prokaryotes and archaea. Humans obtain polyamines through dietary intake, metabolic production, or uptake of polyamines made by gut microbes. The polyamine biosynthetic pathway used by most gut microbes differs from that used by human cells. This alternative pathway employs carboxyspermidine dehydrogenase (CASDH), an enzyme with limited characterization. Here, we solved a 1.94 Å X-ray crystal structure of Bacteroides fragilis CASDH was solved by molecular replacement. BfCASDH is composed of three domains with a fold similar to saccharopine dehydrogenase, but with a distinct active site arrangement. Using steady-state methods, we determined kcat and kcat/Km for BfCASDH and Clostridium leptum CASDH using putrescine, diaminopropane, aspartate semi-aldehyde, NADH and NADPH as substrates. These data revealed evidence of cooperativity in BfCASDH. Putrescine is the likely polyamine substrate and NADPH is the coenzyme used to complete the reaction, forming carboxyspermidine as a product. These data provide the first kinetic characterization of CASDH - a key enzyme in the production of microbial polyamines.

Keywords:  aspartate semialdehyde; carboxyspermidine; dehydrogenase; gut microbiome; norspermidine; polyamine; putrescine; spermidine

DOI:  https://doi.org/10.1016/j.jbc.2023.105033
Int Immunopharmacol. 2023 Jul 07. pii: S1567-5769(23)00918-9. [Epub ahead of print]122 110593

BRG1 mediates protective ability of spermidine to ameliorate osteoarthritic cartilage by Nrf2/KEAP1 and STAT3 signaling pathway.

Xinjie Mao, Bing Yan, Hongjie Chen, Peng Lai, Jinzhong Ma.

  BACKGROUND: Spermidine (SPD) is a natural polyamine that shows beneficial effects on osteoarthritis (OA). However, the effect of SPD on cartilage inflammation remains unknown. This study aimed to investigate the potential mechanisms underlying the protective effect of SPD against OA-induced articular cartilage degradation.METHOD: SW1353 human chondrocytes were treated with hydrogen peroxide and lipopolysaccharide to induce models of inflammation and oxidative stress, followed by different dose of SPD intervention. Moreover, mice that underwent anterior cruciate ligament transection were bred and treated with SPD. The effects of SPD were observed using a CCK-8 kit, real-time polymerase chain reaction, immunoblotting, and immunofluorescent assays.
RESULT: SPD significantly increased the expression of antioxidant proteins, chondrogenic genes, and inflammatory factors both in vivo and in vitro. And injury of the mouse cartilage was also reduced by SPD. Moreover, SPD activated the Nrf2/KEAP1 pathway and inhibited STAT3 phosphorylation. BRG1 expression was decreased in osteoarthritic mouse cartilage, whereas SPD treatment caused an upregulation. However, when BRG1 was specifically inhibited by an adeno-associated virus and small interfering RNA, the antioxidant and anti-inflammatory effects of SPD were significantly diminished both in vitro and in vivo.
CONCLUSION: We found that SPD ameliorated cartilage damage in OA by activating the BRG1-mediated Nrf2/KEAP1 pathway. SPD and BRG1 may provide new therapeutic options or targets for the treatment of OA.

Keywords:  Antioxidant proteins; BRG1; Inflammation; Osteoarthritis; Spermidine

DOI:  https://doi.org/10.1016/j.intimp.2023.110593
Poult Sci. 2023 Jun 18. pii: S0032-5791(23)00398-X. [Epub ahead of print]102(9): 102879

Spermidine alleviating oxidative stress and apoptosis by inducing autophagy of granulosa cells in Sichuan white geese.

Dongmei Jiang, Xin Wang, Xuemin Zhou, Zelong Wang, Shuo Li, Qian Sun, Yilong Jiang, Chengweng Ji, Weikang Ling, Xiaoguang An, Bo Kang.

  Spermidine have been reported a role in antioxidative, antiaging, and antiinflammatory. Oxidative stress causes granulosa cell (GC) apoptosis, follicular atresia, and impairs poultry reproductive functions. Studies have found that autophagy is the protective mechanism against antioxidant stress and apoptosis in cells. However, the relationship between spermidine-induced autophagy, oxidative stress, and apoptosis in goose GCs remains unclear. In this study, we investigated the autophagy mechanism to mediate spermidine effects on the alleviation of oxidative stress and apoptosis in goose GCs. Follicular GCs were treated with spermidine combination with 3-Nitropropanoic acid (3-NPA), rapamycin (RAPA), and chloroquine (CQ) or with hydrogen peroxide, RAPA, and CQ. Spermidine upregulated the ratio of LC3-II/I, inhibited the accumulation of p62 protein, and induced autophagy. 3-NPA treatment significantly increased ROS production, MDA content, SOD activity, cleaved CASPASE-3 protein expression, and decreased BCL-2 protein expression in follicular GCs. Spermidine inhibited oxidative stress and apoptosis induced by 3-NPA. In addition, hydrogen peroxide-induced oxidative stress was inhibited by spermidine. However, the inhibitory effect of spermidine was eliminated under chloroquine. Our results demonstrated that spermidine relieved oxidative stress and apoptosis of GCs by inducing autophagy, indicating that spermidine has a great potential to maintain proteostasis and sustain granulosa cell viability in geese.

Keywords:  apoptosis; autophagy; granulosa cell; oxidative stress; spermidine

DOI:  https://doi.org/10.1016/j.psj.2023.102879
Int J Mol Sci. 2023 Jun 23. pii: 10550. [Epub ahead of print]24(13):

Spermidine Attenuates High Glucose-Induced Oxidative Damage in Retinal Pigment Epithelial Cells by Inhibiting Production of ROS and NF-κB/NLRP3 Inflammasome Pathway.

EunJin Bang, Cheol Park, Hyun Hwangbo, Jung-Hyun Shim, Sun-Hee Leem, Jin Won Hyun, Gi-Young Kim, Yung Hyun Choi.

  Diabetic retinopathy (DR) is the leading cause of vision loss and a critical complication of diabetes with a very complex etiology. The build-up of reactive oxygen species (ROS) due to hyperglycemia is recognized as a primary risk factor for DR. Although spermidine, a naturally occurring polyamine, has been reported to have antioxidant effects, its effectiveness in DR has not yet been examined. Therefore, in this study, we investigated whether spermidine could inhibit high glucose (HG)-promoted oxidative stress in human retinal pigment epithelial (RPE) cells. The results demonstrated that spermidine notably attenuated cytotoxicity and apoptosis in HG-treated RPE ARPE-19 cells, which was related to the inhibition of mitochondrial ROS production. Under HG conditions, interleukin (IL)-1β and IL-18's release levels were markedly increased, coupled with nuclear factor kappa B (NF-κB) signaling activation. However, spermidine counteracted the HG-induced effects. Moreover, the expression of nucleotide-binding oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome multiprotein complex molecules, including TXNIP, NLRP3, ASC, and caspase-1, increased in hyperglycemic ARPE-19 cells, but spermidine reversed these molecular changes. Collectively, our findings demonstrate that spermidine can protect RPE cells from HG-caused injury by reducing ROS and NF-κB/NLRP3 inflammasome pathway activation, indicating that spermidine could be a potential therapeutic compound for DR treatment.

Keywords:  NF-κB; NLRP3 inflammasome; ROS; apoptosis; spermidine

DOI:  https://doi.org/10.3390/ijms241310550