bims-polyam 2024-02-25 papers

Issue of 2024–02–25
six papers selected by
Sebastian J. Hofer, University of Graz

Annu Rev Plant Biol. 2024 Feb 21.

Polyamines: Their Role in Plant Development and Stress.

This review focuses on the intricate relationship between plant polyamines and the genetic circuits and signaling pathways that regulate various developmental programs and the defense responses of plants when faced with biotic and abiotic aggressions. Particular emphasis is placed on genetic evidence supporting the involvement of polyamines in specific processes, such as the pivotal role of thermospermine in regulating xylem cell differentiation and the significant contribution of polyamine metabolism in enhancing plant resilience to drought. Based on the numerous studies describing effects of the manipulation of plant polyamine levels, two conceptually different mechanisms for polyamine activity are discussed: direct participation of polyamines in translational regulation and the indirect production of hydrogen peroxide as a defensive mechanism against pathogens. By describing the multifaceted functions of polyamines, this review underscores the profound significance of these compounds in enabling plants to adapt and thrive in challenging environments. Expected final online publication date for the Annual Review of Plant Biology, Volume 75 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-arplant-070623-110056

Cancer Metab. 2024 Feb 23. 12(1): 7

Elevated expression of HIGD1A drives hepatocellular carcinoma progression by regulating polyamine metabolism through c-Myc-ODC1 nexus.

Haixing Zhang, Xiaoran Li, Ziying Liu, Zimo Lin, Kuiyuan Huang, Yiran Wang, Yu Chen, Leyi Liao, Leyuan Wu, Zhanglian Xie, Jinlin Hou, Xiaoyong Zhang, Hongyan Liu.

BACKGROUND: Hypoxia contributes to cancer progression through various molecular mechanisms and hepatocellular carcinoma (HCC) is one of the most hypoxic malignancies. Hypoxia-inducible gene domain protein-1a (HIGD1A) is typically induced via epigenetic regulation and promotes tumor cell survival during hypoxia. However, the role of HIGD1A in HCC remains unknown.
METHODS: HIGD1A expression was determined in 24 pairs of human HCC samples and para-tumorous tissues. Loss-of-function experiments were conducted both in vivo and in vitro to explore the role of HIGD1A in HCC proliferation and metastasis.
RESULTS: Increased HIGD1A expression was found in HCC tissues and cell lines, which was induced by hypoxia or low-glucose condition. Moreover, HIGD1A knockdown in HCC cells arrested the cell cycle at the G2/M phase and promoted hypoxia-induced cell apoptosis, resulting in great inhibition of cell proliferation, migration, and invasion, as well as tumor xenograft formation. Interestingly, these anti-tumor effects were not observed in normal hepatocyte cell line L02. Further, HIGD1A knockdown suppressed the expression of ornithine decarboxylase 1 (ODC1), a rate-limiting enzyme of polyamine metabolism under c-Myc regulation. HIGD1A was found to bind with the c-Myc promoter region, and its knockdown decreased the levels of polyamine metabolites. Consistently, the inhibitory effect on HCC phenotype by HIGD1A silencing could be reversed by overexpression of c-Myc or supplementation of polyamines.
CONCLUSIONS: Our results demonstrated that HIGD1A activated c-Myc-ODC1 nexus to regulate polyamine synthesis and to promote HCC survival and malignant phenotype, implying that HIGD1A might represent a novel therapeutic target for HCC.

Keywords: Hepatocellular carcinoma (HCC); Hypoxia-induced gene domain protein-1a (HIGD1A); Ornithine decarboxylase 1 (ODC1); Polyamine metabolism; c-Myc

DOI: https://doi.org/10.1186/s40170-024-00334-6

Biomolecules. 2024 Feb 02. pii: 178. [Epub ahead of print]14(2):

Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in Streptococcus pneumoniae.

Moses B Ayoola, Leslie A Shack, Otto Phanstiel, Bindu Nanduri.

Streptococcus pneumoniae (Spn), a Gram-positive bacterium, poses a significant threat to human health, causing mild respiratory infections to severe invasive conditions. Despite the availability of vaccines, challenges persist due to serotype replacement and antibiotic resistance, emphasizing the need for alternative therapeutic strategies. This study explores the intriguing role of polyamines, ubiquitous, small organic cations, in modulating virulence factors, especially the capsule, a crucial determinant of Spn's pathogenicity. Using chemical inhibitors, difluoromethylornithine (DFMO) and AMXT 1501, this research unveils distinct regulatory effects on the gene expression of the Spn D39 serotype in response to altered polyamine homeostasis. DFMO inhibits polyamine biosynthesis, disrupting pathways associated with glucose import and the interconversion of sugars. In contrast, AMXT 1501, targeting polyamine transport, enhances the expression of polyamine and glucose biosynthesis genes, presenting a novel avenue for regulating the capsule independent of glucose availability. Despite ample glucose availability, AMXT 1501 treatment downregulates the glycolytic pathway, fatty acid synthesis, and ATP synthase, crucial for energy production, while upregulating two-component systems responsible for stress management. This suggests a potential shutdown of energy production and capsule biosynthesis, redirecting resources towards stress management. Following DFMO and AMXT 1501 treatments, countermeasures, such as upregulation of stress response genes and ribosomal protein, were observed but appear to be insufficient to overcome the deleterious effects on capsule production. This study highlights the complexity of polyamine-mediated regulation in S. pneumoniae, particularly capsule biosynthesis. Our findings offer valuable insights into potential therapeutic targets for modulating capsules in a polyamine-dependent manner, a promising avenue for intervention against S. pneumoniae infections.

Keywords: AMXT 1501; DFMO; Streptococcus pneumoniae; capsule; polyamine

DOI: https://doi.org/10.3390/biom14020178

Biochim Biophys Acta Mol Basis Dis. 2024 Feb 15. pii: S0925-4439(24)00072-3. [Epub ahead of print]1870(4): 167083

Spermidine ameliorates osteoarthritis via altering macrophage polarization.

Qianhua Ou, Su'an Tang, Jianwei Zhu, Song Xue, Hong Huang, Yang Zhao, Yu Cai, Cuixi Wu, Jianmao Chen, Guangfeng Ruan, Changhai Ding.

OBJECTIVE: Spermidine (SPD) is an anti-aging natural substance, and it exerts effects through anti-apoptosis and anti-inflammation. However, the specific protective mechanism of SPD in osteoarthritis (OA) remains unclear. Here, we explored the role of SPD on the articular cartilage and the synovial tissue, and tested whether the drug would regulate the polarization of synovial macrophages by in vivo and in vitro experiments.
METHODS: By constructing an OA model in mice, we preliminarily explored the protective effect of SPD on the articular cartilage and the synovial tissue. Meanwhile, we isolated and cultured human primary chondrocytes and bone marrow-derived macrophages (BMDMs), and prepared a conditioned medium (CM) to explore the specific protective effect of SPD in vitro.
RESULTS: We found that SPD alleviated cartilage degeneration and synovitis, increased M2 polarization and decreased M1 polarization in synovial macrophages. In vitro experiments, SPD inhibited ERK MAPK and p65/NF-κB signaling in macrophages, and transformed macrophages from M1 to M2 subtypes. Interestingly, SPD had no direct protective effect on chondrocytes in vitro; however, the conditioned medium (CM) from M1 macrophages treated with SPD promoted the anabolism and inhibited the catabolism of chondrocytes. Moreover, this CM markedly suppressed IL-1β-induced p38/JNK MAPK signaling pathway activation in chondrocytes.
CONCLUSIONS: This work provides new perspectives on the role of SPD in OA. SPD does not directly target chondrocytes, but can ameliorate the degradation of articular cartilage through regulating M1/M2 polarization of synovial macrophages. Hence, SPD is expected to be the potential therapy for OA.

Keywords: Chondrocytes; Macrophages; Osteoarthritis; Polarization; Spermidine

DOI: https://doi.org/10.1016/j.bbadis.2024.167083

Cell Commun Signal. 2024 Feb 20. 22(1): 139

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis.

Peng Gao, Jianyou Wang, Huan Tang, Huanhuan Pang, Jiemei Liu, Chen Wang, Fei Xia, Honglin Chen, Liting Xu, Junzhe Zhang, Lixia Yuan, Guang Han, Jigang Wang, Gang Liu.

BACKGROUND: Malaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive.
METHODS: We first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays.
RESULTS: The results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-α were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects.
CONCLUSIONS: In conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel. Video Abstract.

Keywords: Antimalarial; Celastrol; Protein synthesis; Spermidine

DOI: https://doi.org/10.1186/s12964-023-01409-5