polyamine synthesis
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2021 ◽  
Author(s):  
Tianrui Zhang ◽  
Yingying Zheng ◽  
Tianya Kuang ◽  
Lianyu Yang ◽  
Hailong Jiang ◽  
...  

Abstract Background:Arginine has a positive effect on preimplantation development in pigs. However, the exact mechanism by which arginine promotes embryonic development to the blastocyst stage is not undefined. Here, single-cell RNA-sequencing technology was applied to porcine in vivo pre-implantation embryos from zygote to morula to determine transcription patterns of arginine metabolism-related genes during preimplantation embryonic development.Results:Transcriptome sequencing showed that arginine metabolism-related genes clearly changed from the 2-cell stage to the 4-cell stage, where zygotic genome activation (ZGA) occurred in porcine embryos. Further analysis of the correlation between arginine metabolism and ZGA shows that arginine metabolism-related genes are significantly correlated with key ZGA genes such as ZSCAN4, DPPA2 and EIF1A, indicating that arginine metabolism may be an indicator of porcine ZGA. To explore the correlation between arginine metabolism and ZGA, embryos cultured in the medium that removes all the amino acids, proteins and pyruvate in the PZM3 medium were employed to generate the ZGA blocked embryo model. The 4-cell arrest rate significantly increased at 72 h after activation, indicating impeded embryonic development. Meanwhile, results of immunofluorescent staining showed that the expression of SIRT1 protein during ZGA was significantly inhibited. Results of quantitative PCR showed that the expression of zygotic genes (ZSCAN4, DPPA2 and EIF1A) was significantly decreased. The above results indicate that the ZGA blocked embryo model was successfully established. Adding of arginine recovered embryonic development, SIRT1 and zygotic genes expression levels and initiated the ZGA. In addition, ROS content significantly increased when ZGA was blocked, and the GSH, ATP and lipid droplet content significantly decreased. After the addition of arginine in the block group, the ROS content significantly decreased, and the GSH, ATP and lipid droplet content significantly increased. Moreover, the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) and arginine were added to the block group at the same time, and the effect of arginine was found to be inhibited. Conclusions: Arginine is essential for ZGA in porcine embryos. Arginine contributes to porcine ZGA by promoting polyamine synthesis in porcine embryos.


2021 ◽  
Vol 21 (12) ◽  
Author(s):  
Tyler N. Kambis ◽  
Hadassha M. N. Tofilau ◽  
Flobater I. Gawargi ◽  
Surabhi Chandra ◽  
Paras K. Mishra

Abstract Purpose of Review Insulin is at the heart of diabetes mellitus (DM). DM alters cardiac metabolism causing cardiomyopathy, ultimately leading to heart failure. Polyamines, organic compounds synthesized by cardiomyocytes, have an insulin-like activity and effect on glucose metabolism, making them metabolites of interest in the DM heart. This review sheds light on the disrupted microRNA network in the DM heart in relation to developing novel therapeutics targeting polyamine biosynthesis to prevent/mitigate diabetic cardiomyopathy. Recent Findings Polyamines prevent DM-induced upregulation of glucose and ketone body levels similar to insulin. Polyamines also enhance mitochondrial respiration and thereby regulate all major metabolic pathways. Non-coding microRNAs regulate a majority of the biological pathways in our body by modulating gene expression via mRNA degradation or translational repression. However, the role of miRNA in polyamine biosynthesis in the DM heart remains unclear. Summary This review discusses the regulation of polyamine synthesis and metabolism, and its impact on cardiac metabolism and circulating levels of glucose, insulin, and ketone bodies. We provide insights on potential roles of polyamines in diabetic cardiomyopathy and putative miRNAs that could regulate polyamine biosynthesis in the DM heart. Future studies will unravel the regulatory roles these miRNAs play in polyamine biosynthesis and will open new doors in the prevention/treatment of adverse cardiac remodeling in diabetic cardiomyopathy.


Author(s):  
Min-Sik Lee ◽  
Insia Naqvi ◽  
Courtney Dennis ◽  
Lucas Dailey ◽  
Alireza Lorzadeh ◽  
...  

2021 ◽  
Author(s):  
Xinyi Shen ◽  
Yuping Cai ◽  
Lingeng Lu ◽  
Huang Huang ◽  
Hong Yan ◽  
...  

Abstract Background The interplay between the sex-specific differences in tumor metabolome and colorectal cancer (CRC) prognosis has never been studied and represents an opportunity to improve patient outcomes. This study aims to examine the link between tumor metabolome and prognosis by sex for CRC patients. Methods Using untargeted metabolomics analysis, abundances of 91 metabolites were obtained from primary tumor tissues from 197 patients (N=95 females, N=102 males) after surgical colectomy for stage I-III CRC. Cox Proportional Hazards (PH) regression models were applied to estimate the associations between tumor metabolome and 5-year overall survival (OS) and 5-year recurrence-free survival (RFS), and their interactions with sex. Results Eleven metabolites had significant sex differences in their associations with 5-year OS, and five metabolites for 5-year RFS (Pinteraction < .05). The metabolites asparagine and serine had sex interactions for both OS and RFS. Furthermore, sex-specific differences were found in the associations between prognosis and metabolic pathways. Notably, in the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway, asparagine was associated with substantially poorer OS (hazard ratio [HR] = 6.39, 95% confidence interval [CI] = 1.78-22.91, P = .004) and RFS (HR = 4.36, 95% CI = 1.39-13.68, P = .01) for female patients only (Pinteraction, OS = .02, Pinteraction, RFS = .003). Similar prognostic disadvantages in females were seen in lysophospholipid and polyamine synthesis. Conclusions Unique metabolite profiles indicated increased asparagine synthesis was associated with poorer prognosis for females only, providing insights into precision medicine for CRC treatment stratified by sex.


Amino Acids ◽  
2021 ◽  
Author(s):  
Kyohei Furukawa ◽  
Wenliang He ◽  
Christopher A. Bailey ◽  
Fuller W. Bazer ◽  
Masaaki Toyomizu ◽  
...  
Keyword(s):  

2021 ◽  
Vol 15 (7) ◽  
pp. e0009583
Author(s):  
Mikael Boberg ◽  
Monica Cal ◽  
Marcel Kaiser ◽  
Rasmus Jansson-Löfmark ◽  
Pascal Mäser ◽  
...  

The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. The study compared the in vitro antitrypanosomal activity of the two enantiomers with the racemic mixture against three Trypanosoma brucei gambiense strains. Antitrypanosomal in vitro activity at varying drug concentrations was analysed by non-linear mixed effects modelling. For all three strains, L-eflornithine was more potent than D-eflornithine. Estimated 50% inhibitory concentrations of the three strains combined were 9.1 μM (95% confidence interval [8.1; 10]), 5.5 μM [4.5; 6.6], and 50 μM [42; 57] for racemic eflornithine, L-eflornithine and D-eflornithine, respectively. The higher in vitro potency of L-eflornithine warrants further studies to assess its potential for improving the treatment of late-stage Gambian human African trypanosomiasis.


2021 ◽  
Author(s):  
Bodhisattwa Banerjee ◽  
Iryna Khrystoforova ◽  
Baruh Polis ◽  
David Karasik

Abstract Living organisms repeatedly encounter stressful events and apply various strategies to survive. Polyamines are omnipresent bioactive molecules with multiple functions. Their transient synthesis, inducible by numerous stressful stimuli, is termed the polyamine stress response. Animals developed evolutionary-conserved strategies to cope with stresses. The urea cycle is an ancient attribute that deals with ammonia excess in terrestrial species. Remarkably, most fish retain the urea cycle genes fully expressed during the early stages of development and silenced in adult animals. Environmental challenges instigate urea synthesis in fish despite substantial energetic costs, which poses a question of the urea cycle's evolutionary significance. Arginase plays a critical role in oxidative stress-dependent reactions being the final urea cycle' enzyme. Its unique subcellular localization, high inducibility, several regulation levels provide a supreme ability to control the polyamine synthesis rate. Of note, oxidative stress instigates the arginase-1 activity in mammals. Arginase is also dysregulated in aging organisms' brain and muscle tissues, indicating its role in the pathogenesis of age-associated diseases. We designed a study to investigate the levels of the urea cycle and polyamine synthesis-related enzymes in a fish model of acute hypoxia. We evidence synchronized elevation of arginase-2 and ornithine decarboxylase following oxidative stress in adult fish and aging animals that underlines the specific function of arginase-2 in fish. Moreover, we demonstrate oxidative stress-associated polyamine synthesis' induction and urea cycle' arrest in adult fish. The subcellular arginase localization found in the fish seems to correspond to its possible evolutionary roles.


2021 ◽  
Author(s):  
Surabhi Chandra ◽  
Caleb C. Capellen ◽  
Jose A. Ortega ◽  
M. Jane Morwitzer ◽  
Hadassha Tofilau ◽  
...  

Abstract Several cancer subtypes (pancreatic, breast, liver, and colorectal) rapidly advance to higher aggressive stages in diabetes. Though hyperglycemia has been considered as a fuel for growth of cancer cells, pathways leading to this condition are still under investigation. Cellular polyamines can modulate normal and cancer cell growth, and inhibitors of polyamine synthesis have been approved for treating colon cancer, however the role of polyamines in diabetes-mediated cancer advancement is unclear as yet. We hypothesized that polyamine metabolic pathway is involved with increased proliferation of breast cancer cells under high glucose(HG) conditions. Studies were performed with varying concentrations of glucose (5mM-25mM) exposure in invasive, triple negative breast cancer cells, MDA-MB-231; non-invasive, estrogen/progesterone receptor positive breast cancer cells, MCF-7; and non-tumorigenic mammary epithelial cells, MCF-10A. There was a significant increase in proliferation with HG (25mM) at 48-72h in both MDA-MB-231 and MCF-10A cells but no such effect was observed in MCF-7 cells. This was correlated to higher activity of ornithine decarboxylase (ODC), the rate limiting enzyme in polyamine synthesis pathway. Inhibitor of polyamine synthesis (difluoromethylornithine, DFMO, 5mM) was quite effective in suppressing HG-mediated cell proliferation and ODC activity in MDA-MB-231 and MCF-10A cells. Polyamine (putrescine) levels were significantly elevated with HG treatment in MDA-MB-231 cells. HG exposure also increased the metastasis of MDA-MB-231 cells. Our findings are the first to indicate that polyamine inhibition can improve prognosis of breast cancer patients with diabetes, and also prevent proliferation of normal breast epithelial cells, which could potentially become tumorigenic.


2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i40-i41
Author(s):  
Aaminah Khan ◽  
Laura Gamble ◽  
Dannielle Upton ◽  
Denise Yu ◽  
Ruby Pandher ◽  
...  

Abstract Diffuse intrinsic pontine glioma (DIPG) is an aggressive paediatric brainstem tumour, with a median survival of less than 1 year. Polyamines are intracellular polycations that control important aspects of cell growth and are often upregulated in cancer. Difluoromethylornithine (DFMO) is an FDA-approved inhibitor of the enzyme ornithine decarboxylase (ODC1) which is a key driver of polyamine synthesis. We investigated the efficacy of polyamine pathway inhibitors as a therapeutic strategy against DIPG. We found that there were high over-expression levels of polyamine synthetic enzymes from DIPG primary patient samples and neurosphere cultures. Using alamar blue cytotoxicity and soft-agar clonogenic assays, we found that DFMO inhibited the proliferation of DIPG neurospheres. However, DIPG cells compensated for DFMO inhibition by increasing expression of the polyamine transporter SLC3A2 and subsequently uptake of polyamines. Addition of polyamine transporter inhibitor AMXT 1501 to DFMO led to synergistic inhibition of DIPG proliferation in vitro. Consistent with the in vitro results, the combination of DFMO and AMXT 1501 significantly prolonged the survival of mice bearing 3 different DIPG orthografts with at least 2/3 of the animals surviving up to 160 days. Addition of irradiation further improved the survival of mice treated with DFMO and AMXT 1501. Differential expression analysis showed that the polyamine transporter, SLC3A2, was significantly overexpressed in DIPG and other paediatric brain tumours including high grade gliomas compared with normal brain tissue. Our results suggest that DIPG tumours are exquisitely sensitive to polyamine inhibitors, and that dual blockade of polyamine synthesis and transport is a promising novel therapeutic strategy. AMXT 1501 is currently in clinical development, and following completion of an adult Phase 1 trial, a clinical trial of AMXT 1501 + DFMO for DIPG patients is planned through the CONNECT consortium.


2021 ◽  
Vol 11 ◽  
Author(s):  
Hongyan Ma ◽  
Qizhang Li ◽  
Jing Wang ◽  
Jing Pan ◽  
Zhengding Su ◽  
...  

Personized treatment of breast cancer is still a challenge, and more treatment options for breast cancer are warranted. Combination therapies have been a highly appreciated strategy for breast cancer treatment in recent years, and the development of new combination therapies could improve patient outcomes. Adenosine and polyamines are both endogenous metabolites with indispensable biological functions. Adenosine binds with the A1 adenosine receptor (A1AR) to downregulate cAMP concentration, and both low cAMP content and high polyamine levels stimulate the growth and proliferation of cancer cells. In this work, we initially used a polyamine synthesis inhibitor, DFMO (α-difluoromethylornithine), and an A1AR inhibitor, DPCPX (8-cyclopentyl-1,3-dipropylxanthine) to investigate if simultaneously inhibiting A1AR and polyamine synthesis has synergistical antitumor effects. Next, we investigated a dual inhibitor (ODC-MPI-2) of A1AR and ODC (ornithine decarboxylase 1), the rate-limiting enzyme in polyamine biosynthesis. We investigated if ODC-MPI-2 could inhibit the proliferation and growth of breast cancer cells. Our data showed that DFMO and DPCPX synergistically inhibit the growth and proliferation of MCF-7 cells. We also demonstrated that ODC-MPI-2 reduces cellular polyamine levels and elevates cAMP concentration. We further showed that ODC-MPI-2 inhibits the growth, proliferation, and migration/invasion of MCF-7 cells. Finally, ODC-MPI-2 showed a preference for inhibiting triple-negative breast cancer cells. The dual inhibition of ODC and A1AR is a new combination therapy strategy for treating breast cancer, and dual inhibitors of ODC and A1AR may be effective future drugs for treating breast cancer.


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