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Association between ornithine (per 1-SD increase) and breast cancer by pathological stages of diagnosis and tumor grades. aOdds ratio and P for trend were adjusted for age, body mass index, age at menarche, hypertension diagnosis, type II diabetes diagnosis, history of cancer, smoking, alcohol consumption, family history of cancer, postmenopausal status, and parity. Bold values are statistically significant at α = 0.05.
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In vivo and vitro evidence indicates that ornithine and its related metabolic products play a role in tumor development. Whether ornithine is associated with breast cancer in humans is still unclear. We examined the association between circulating ornithine levels and breast cancer in females. This 1:1 age-matched case-control study identified 735...
Citations
... Ornithine is a ubiquitous nonessential amino acid whose role in growth was partially elucidated early on. Studies have shown that ornithine utilization is higher in cancer patients compared to normal subjects (Webber et al. 1980;Muhling et al. 2004), with the excessive synthesis of polyamines from ornithine in the presence of a series of enzymes, which plays a vital role in regulating cancer progression (Vargas-Ramirez et al. 2016;Zhang et al. 2020;Sivashanmugam et al. 2017). Polyamines are naturally occurring polycationic alkylamines and are ubiquitously present in minute concentrations in all mammalian cells and are involved in many fundamental processes of cell growth and transformation (Igarashi and Kashiwagi 2019;Michael 2016;Agostinelli 2020). ...
Ornithine metabolism plays a vital role in tumorigenesis. For cancer cells, ornithine is mainly used as a substrate for ornithine decarboxylase (ODC) for the synthesis of polyamines. The ODC as a key enzyme of polyamine metabolism has become an important target for cancer diagnosis and treatment. To non-invasively detect the levels of ODC expression in malignant tumors, we have synthesized a novel ⁶⁸Ga-labeled ornithine derivative ([⁶⁸Ga]Ga-NOTA-Orn). The synthesis time of [⁶⁸Ga]Ga-NOTA-Orn was about 30 min with a radiochemical yield of 45–50% (uncorrected), and the radiochemical purity was > 98%. [⁶⁸Ga]Ga-NOTA-Orn was stable in saline and rat serum. Cellular uptake and competitive inhibition assays using DU145 and AR42J cells demonstrated that the transport pathway of [⁶⁸Ga]Ga-NOTA-Orn was similar to that of l-ornithine, and it could interact with the ODC after transporting into the cell. Biodistribution and micro-positron emission tomography (Micro-PET) imaging studies showed that [⁶⁸Ga]Ga-NOTA-Orn exhibited rapid tumor uptake and was rapidly excreted through the urinary system. All above results suggested that [⁶⁸Ga]Ga-NOTA-Orn is a novel amino acid metabolic imaging agent with great potential of tumor diagnosis.
... Only 16 metabolites (2.4%) were identified by at least five papers as significantly changing between healthy controls and PDAC patients. Notably, glutamate (11 studies), glutamine (10 studies), and ornithine (9 studies) were the metabolites identified in most studies and all have established roles in cancer [43][44][45]. Table 1. The numbers colored red corresponds to studies that used either plasma or serum samples. ...
... Only 16 metabolites (2.4%) were identified by at least five papers as significantly changing between healthy controls and PDAC patients. Notably, glutamate (11 studies), glutamine (10 studies), and ornithine (9 studies) were the metabolites identified in most studies and all have established roles in cancer [43][44][45]. can be found in Supplemental Table S1A. For all metabolites with only a single occurrence, the metabolites are ordered alphabetically. ...
Clinical metabolomics is a rapidly expanding field focused on identifying molecular biomarkers to aid in the efficient diagnosis and treatment of human diseases. Variations in study design, metabolomics methodologies, and investigator protocols raise serious concerns about the accuracy and reproducibility of these potential biomarkers. The explosive growth of the field has led to the recent availability of numerous replicate clinical studies, which permits an evaluation of the consistency of biomarkers identified across multiple metabolomics projects. Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death and has the lowest five-year survival rate primarily due to the lack of an early diagnosis and the limited treatment options. Accordingly, PDAC has been a popular target of clinical metabolomics studies. We compiled 24 PDAC metabolomics studies from the scientific literature for a detailed meta-analysis. A consistent identification across these multiple studies allowed for the validation of potential clinical biomarkers of PDAC while also highlighting variations in study protocols that may explain poor reproducibility. Our meta-analysis identified 10 metabolites that may serve as PDAC biomarkers and warrant further investigation. However, 87% of the 655 metabolites identified as potential biomarkers were identified in single studies. Differences in cohort size and demographics, p-value choice, fold-change significance, sample type, handling and storage, data collection, and analysis were all factors that likely contributed to this apparently large false positive rate. Our meta-analysis demonstrated the need for consistent experimental design and normalized practices to accurately leverage clinical metabolomics data for reliable and reproducible biomarker discovery.
... В сравнительном клиническом исследовании более высокие уровни орнитина в крови были ассоциированы с более низким риском рака груди у пациенток 50+-9 лет (735 случаев, 735 контролей). Повышение уровня орнитина на 10 мкмоль/л было ассоциировано со снижением риска рака груди на 12% (ОШ 0,88; 95% ДИ 0,79-0,97) [10]. ...
This analysis of 21,626 publications on fundamental and clinical studies of ornithine showed that the pharmacological effects of ornithine are due to its participation in the neutralization of ammonia in the urea cycle, amino acid metabolism, intracellular protein synthesis, inflammation and the functioning of T-cell immunity. The use of ornithine is promising for hyperammonemia, steatohepatosis and other liver pathologies, hepatic encephalopathy and sarcopenia. Ornithine maintains hormonal balance by promoting the production of insulin and growth hormone.
... Ornithine also plays an important role in the regulation of several metabolic processes leading to diseases like hyperornithinemia, hyperammonemia, gyrate atrophy, and cancer in humans [64]. High levels of ornithine have been reported to be a potential protective factor for BC [65]. Similarly, as we demonstrated for metastatic MDA-MB-231 cell line, OAT is overexpressed in hepatocellular carcinoma, and the inhibition of this enzyme has been suggested to be an effective therapy in mice [66,67]. ...
Membrane-derived extracellular vesicles, referred to as microvesicles (MVs), have been proposed to participate in several cancer diseases. In this study, MV fractions were isolated by differential ultracentrifugation from a metastatic breast cancer (BC) cell line MDA-MB-231 and a non-cancerous breast cell line MCF10A, then analyzed by nano-liquid chromatography coupled to tandem mass spectrometry. A total of 1519 MV proteins were identified from both cell lines. The data obtained were compared to previously analyzed proteins from small extracellular vesicles (sEVs), revealing 1272 proteins present in both MVs and sEVs derived from the MDA-MB-231 cell line. Among the 89 proteins unique to MDA-MB-231 MVs, three enzymes: ornithine aminotransferase (OAT), transaldolase (TALDO1) and bleomycin hydrolase (BLMH) were previously proposed as cancer therapy targets. These proteins were enzymatically validated in cells, sEVs, and MVs derived from both cell lines. The specific activity of OAT and TALDO1 was significantly higher in MDA-MB-231-derived MVs than in MCF10A MVs. BLMH was highly expressed in MDA-MB-231-derived MVs, compared to MCF10A MVs. This study shows that MVs carry functional metabolic enzymes and provides a framework for future studies of their biological role in BC and potential in therapeutic applications.
Global warming threatens freshwater ecosystems and compromises fish survival. To elucidate the role of miRNAs in the livers of heat stressed largemouth bass, juvenile fish was subject to heat stress under 37 °C. Both mRNA-seq and miRNA-seq were conducted on the liver tissues under control and heat stress conditions. Differential gene expression analysis and enrichment analysis were performed on mRNA and miRNA expression profiles. A total of 406 differentially expressed genes (DEGs) were discovered, of which 212 were up-regulated and 194 were down-regulated. Most of the DEGs were significantly implicated in the regulation of “protein processing in endoplasmic reticulum”, “proteasome”, “steroid biosynthesis”, and “ornithine decarboxylase inhibitor activity” pathways. In addition, 47 differentially expressed miRNAs (DEMs) were identified in largemouth bass livers under heat stress, including 21 up-regulated and 25 down-regulated miRNAs. A negatively regulated miRNA-mRNA network including 12 miRNAs and 19 mRNAs was constructed with DEMs involved in “protein degradation”, “calcium ion regulation”, “cell apoptosis”, and “lipid metabolism”. Moreover, this study indicated novel-miR-144 activated the IRE1 signaling pathway by targeting txndc5 to induce liver apoptosis in largemouth bass under heat stress. This study revealed the involvement of miRNA regulation in largemouth bass in response to heat stress.
This review summarizes the role of amino acids in the diagnosis, risk assessment, imaging, and treatment of breast cancer. It was shown that the content of individual amino acids changes in breast cancer by an average of 10–15% compared with healthy controls. For some amino acids (Thr, Arg, Met, and Ser), an increase in concentration is more often observed in breast cancer, and for others, a decrease is observed (Asp, Pro, Trp, and His). The accuracy of diagnostics using individual amino acids is low and increases when a number of amino acids are combined with each other or with other metabolites. Gln/Glu, Asp, Arg, Leu/Ile, Lys, and Orn have the greatest significance in assessing the risk of breast cancer. The variability in the amino acid composition of biological fluids was shown to depend on the breast cancer phenotype, as well as the age, race, and menopausal status of patients. In general, the analysis of changes in the amino acid metabolism in breast cancer is a promising strategy not only for diagnosis, but also for developing new therapeutic agents, monitoring the treatment process, correcting complications after treatment, and evaluating survival rates.
Background:
Lipidomics and metabolomics are closely related to tumor phenotypes, and serum lipoprotein subclasses and small-molecule metabolites are considered as promising biomarkers for breast cancer (BC) diagnosis. This study aimed to explore potential biomarker models based on lipidomic and metabolomic analysis that could distinguish BC from healthy controls (HCs) and triple-negative BC (TNBC) from non-TNBC.
Methods:
Blood samples were collected from 114 patients with BC and 75 HCs. A total of 112 types of lipoprotein subclasses and 30 types of small-molecule metabolites in the serum were detected by 1 H-NMR. All lipoprotein subclasses and small-molecule metabolites were subjected to a three-step screening process in the order of significance (p < 0.05), univariate regression (p < 0.1), and lasso regression (nonzero coefficient). Discriminant models of BC versus HCs and TNBC versus non-TNBC were established using binary logistic regression.
Results:
We developed a valid discriminant model based on three-biomarker panel (formic acid, TPA2, and L6TG) that could distinguish patients with BC from HCs. The area under the receiver operating characteristic curve (AUC) was 0.999 (95% confidence interval [CI]: 0.995-1.000) and 0.990 (95% CI: 0.959-1.000) in the training and validation sets, respectively. Based on the panel (D-dimer, CA15-3, CEA, L5CH, glutamine, and ornithine), a discriminant model was established to differentiate between TNBC and non-TNBC, with AUC of 0.892 (95% CI: 0.778-0.967) and 0.905 (95% CI: 0.754-0.987) in the training and validation sets, respectively.
Conclusion:
This study revealed lipidomic and metabolomic differences between BC versus HCs and TNBC versus non-TNBC. Two validated discriminatory models established against lipidomic and metabolomic differences can accurately distinguish BC from HCs and TNBC from non-TNBC.
Impact:
Two validated discriminatory models can be used for early BC screening and help BC patients avoid time-consuming, expensive, and dangerous BC screening.
Ornithine metabolism plays a vital role in tumorigenesis. For cancer cells, ornithine is mainly used as a substrate for ornithine decarboxylase (ODC) to produce amounts of polyamines. The ODC as a key enzyme of polyamine metabolism has become an important target for cancer diagnosis and treatment. To non-invasively detect the levels of ODC expression in malignant tumors, we have synthesized a novel ⁶⁸ Ga-labeled ornithine analog ( ⁶⁸ Ga-NOTA-Orn). The synthesis time of ⁶⁸ Ga-NOTA-Orn was about 30 min with a radiochemical yield of 45–50% (uncorrected), and the radiochemical purity was > 98%. ⁶⁸ Ga-NOTA-Orn was stable in saline and rat serum. Cellular uptake and competitive inhibition assays using DU145 and AR42J cells demonstrated that the transport pathway of ⁶⁸ Ga-NOTA-Orn was similar to that of L-ornithine, and it could interact with the ODC after transporting into the cell. Biodistribution and micro-positron emission tomography (Micro-PET) imaging studies showed that ⁶⁸ Ga-NOTA-Orn exhibited rapid tumor uptake and was rapidly excreted through the urinary system. All above results suggested that ⁶⁸ Ga-NOTA-Orn is a novel amino acid metabolic imaging agent with great potential of tumor diagnosis.
