Pirin Promotes the Progression of Non-Small-Cell Lung Cancer by Increasing ODC1 to Suppress Autophagy.

Non-small-cell lung cancer (NSCLC), a common malignant tumor, requires deeper pathogenesis investigation. Autophagy is an evolutionarily conserved lysosomal degradation process that is frequently blocked during cancer progression. It is an urgent need to determine the novel autophagy-associated regulators in NSCLC. Here, we found that pirin was upregulated in NSCLC, and its expression was positively correlated with poor prognosis. Overexpression of pirin inhibited autophagy and promoted NSCLC proliferation. We then performed data-independent acquisition-based quantitative proteomics to identify the differentially expressed proteins (DEPs) in pirin-overexpression (OE) or pirin-knockdown (KD) cells. Among the pirin-regulated DEPs, ornithine decarboxylase 1 (ODC1) was downregulated in pirin-KD cells while upregulated along with pirin overexpression. ODC1 depletion reversed the pirin-induced autophagy inhibition and pro-proliferation effect in A549 and H460 cells. Immunohistochemistry showed that ODC1 was highly expressed in NSCLC cancer tissues and positively related with pirin. Notably, NSCLC patients with pirinhigh/ODC1high had a higher risk in terms of overall survival. In summary, we identified pirin and ODC1 as a novel cluster of prognostic biomarkers for NSCLC and highlighted the potential oncogenic role of the pirin/ODC1/autophagy axis in this cancer type. Targeting this pathway represents a possible therapeutic approach to treat NSCLC.

An in vitro study of irrigation rate, operator duty cycle and intrarenal temperature in superpulse fiber thulium laser lithotripsy.

OBJECTIVE: The present study aimed to examine the relationship between irrigation velocity, operator duty cycle (ODC), and intrarenal temperature during retrograde intrarenal surgery with a superpulse fiber thulium laser. METHODS: Place the stones into the fresh isolated porcine kidneys, use puncture needle to place the temperature probe 2 mm around the stones, and place the pressure probes in the upper calyx, lower calyx, and renal pelvis. Place the entire setup in a 37 °C constant temperature water bath to simulate the human body environment. The laser power varies between 10 and 30 W, and the irrigation speed is 10-30 ml/min. Additionally, at a laser power of 20 W and an irrigation speed of 10 ml/min, different On-Duty Cycles (ODC) are set. Monitor the changes in temperature and pressure. RESULTS: A direct proportionality of temperature in the kidney to the rate of irrigation has been reported between 10 W and 30 W laser powers. The percentage ratio of the rate of irrigation and power in the laser is 1:1, which can keep the temperature in the kidney at a safe level. At a laser power of 20 W and irrigation of 10 ml/min, the temperature inside the kidney increases sharply with the increase in ODC. By decreasing the ratio of ODC, the increase of temperature inside the kidney can be brought to a great reduction. CONCLUSION: Maintaining a 1:1 ratio between laser power and irrigation speed can effectively prevent thermal damage or injury to kidney tissue.Additionally, by adjusting the On-Duty Cycle (ODC) ratio, the intrarenal temperature can also be reduced.

Enzymatic properties of ornithine decarboxylase from Clostridium aceticum DSM1496.

Clostridium aceticum DSM1496 is an acid-resistant strain in which ornithine decarboxylase (ODC) plays a crucial role in acid resistance. In this study, we expressed ODC derived from C. aceticum DSM1496 in Escherichia coli BL21 (DE3) and thoroughly examined its enzymatic properties. The enzyme has a molecular weight of 55.27 kDa and uses pyridoxal-5'-phosphate (PLP) as a coenzyme with a Km = 0.31 mM. ODC exhibits optimal activity at pH 7.5, and it maintains high stability even at pH 4.5. The peak reaction temperature for ODC is 30°C. Besides, it can be influenced by certain metal ions such as Mn2+. Although l-ornithine serves as the preferred substrate for ODC, the enzyme also decarboxylates l-arginine and l-lysine simultaneously. The results indicate that ODC derived from C. aceticum DSM1496 exhibits the ability to produce putrescine, cadaverine, and agmatine through decarboxylation. These polyamines have the potential to neutralize acid in an acidic environment, facilitating the growth of microorganisms. These significant findings provide a strong basis for further investigation into the acid-resistant mechanisms contributed by ODC.

Preventing Cancer by Inhibiting Ornithine Decarboxylase: A Comparative Perspective on Synthetic vs. Natural Drugs.

This perspective delves into the investigation of synthetic and naturally occurring inhibitors, their patterns of inhibition, and the effectiveness of newly utilized natural compounds as inhibitors targeting the Ornithine decarboxylase enzyme. This enzyme is known to target the MYC oncogene, thereby establishing a connection between polyamine metabolism and oncogenesis in both normal and cancerous cells. ODC activation and heightened polyamine activity are associated with tumor development in numerous cancers and fluctuations in ODC protein levels exert a profound influence on cellular activity for inhibition or suppressing tumor cells. This perspective outlines efforts to develop novel drugs, evaluate natural compounds, and identify promising inhibitors to address gaps in cancer prevention, highlighting the potential of newly designed synthetic moieties and natural flavonoids as alternatives. It also discusses natural compounds with potential as enhanced inhibitors.

Positive Regulation of S-Adenosylmethionine on Chondrocytic Differentiation via Stimulation of Polyamine Production and the Gene Expression of Chondrogenic Differentiation Factors.

S-adenosylmethionine (SAM) is considered to be a useful therapeutic agent for degenerative cartilage diseases, although its mechanism is not clear. We previously found that polyamines stimulate the expression of differentiated phenotype of chondrocytes. We also found that the cellular communication network factor 2 (CCN2) played a huge role in the proliferation and differentiation of chondrocytes. Therefore, we hypothesized that polyamines and CCN2 could be involved in the chondroprotective action of SAM. In this study, we initially found that exogenous SAM enhanced proteoglycan production but not cell proliferation in human chondrocyte-like cell line-2/8 (HCS-2/8) cells. Moreover, SAM enhanced gene expression of cartilage-specific matrix (aggrecan and type II collagen), Sry-Box transcription factor 9 (SOX9), CCN2, and chondroitin sulfate biosynthetic enzymes. The blockade of the methionine adenosyltransferase 2A (MAT2A) enzyme catalyzing intracellular SAM biosynthesis restrained the effect of SAM on chondrocytes. The polyamine level in chondrocytes was higher in SAM-treated culture than control culture. Additionally, Alcian blue staining and RT-qPCR indicated that the effects of SAM on the production and gene expression of aggrecan were reduced by the inhibition of polyamine synthesis. These results suggest that the stimulation of polyamine synthesis and gene expression of chondrogenic differentiation factors, such as CCN2, account for the mechanism underlying the action of SAM on chondrocytes.

A novel kinase subverts aluminium resistance by boosting ornithine decarboxylase-dependent putrescine biosynthesis.

Rice, as one of the most aluminium (Al)-resistant cereal crops, has developed more complicated Al resistance mechanisms than others. By using forward genetic screening from a rice ethyl methanesulfonate mutant library, we obtained a mutant showing specifically high sensitivity to Al. Through MutMap analysis followed by a complementation test, we identified the causal gene, Al-related Protein Kinase (ArPK) for Al-sensitivity. ArPK expression was induced by a relatively longer exposure to high Al concentration in the roots. The result of RNA-sequencing indicated the functional disorder in arginine metabolism pathway with downregulation of N-acetylornithine deacetylase (NAOD) expression and upregulation of Ornithine decarboxylase1 (ODC1) expression in arpk mutant. Al specifically and rapidly upregulated ODC1 expression and causes overaccumulation of putrescine (Put), whereas the ODC inhibitor difluoromethylornithine reverted Al-sensitive phenotype of arpk, suggesting that overaccumulation of endogenous Put might be harmful for root growth, and that ArPK seems to act as an endogenous inhibitor of ODC1 action to maintain suitable endogenous Put level under Al treatment. Overall, we identified ArPK and its putative repressive role in controlling a novel ODC-dependent Put biosynthesis pathway specifically affecting rice Al resistance, thus enriching the fundamental understanding of plant Al resistance.

miR27a, a fine-tuning molecule, interacts with growth hormone (GH) signaling and ornithine decarboxylase (ODC) via targeting STAT5.

Autocrine growth hormone (GH) expression triggers cell proliferation, invasion-metastasis in vitro and in vivo models, but GH gene mutations inhibit postnatal growth. Natural polyamines (PA); putrescine, spermidine, spermine trigger cell growth and differentiation. The importance of miR27a has shown to exert a suppressive effect on ornithine decarboxylase (ODC) expression in dwarf mice models. We aimed to modulate the role of A13S, F166Δ, T24 GH gene mutations' impact on PA metabolism and epithelial-mesencyhmal transition (EMT) pathway through miR27a. Biologically active GH signaling triggered cell viability, growth, and colony formation, but T24A alteration significantly decreases aggressive profiles due to inactive GH signaling through a decline in STAT5 activity and expressions of STAT5, c-myc and ODC. Although statistically significant increase in intracellular PA levels in wt GH signaling HEK293 cells compared to HEK293 cells with a lack of GH signaling, a sharp decline in PA levels measured in each mutant GH expressing HEK293 cells. When we inhibited miR27a, proliferation and colony formation accelerated through a significant increase in putrescine levels and upregulation of ODC, STAT5 expression. In contrast, a substantial decline in GH-mediated colony enlargement observed via ODC, STAT5 downregulation, and PA depletion in both wt and mutant GH expressing HEK293 cell lines by miR27a mimic transfection. In conclusion, T24A mutant GH expression declines the GH signaling through STAT5 activity, and mutant GH signaling decreased cell proliferation, division, and colony formation via EMT inhibition. The autocrine GH-mediated proliferative profiles were under the control of miR27a that depletes intracellular putrescine levels via targeting ODC.

Investigation of Staphylococcus lugdunensis and Selected Coagulase Negative Staphylococci Isolated from Blood Culture bottles and Determination of their Sensitivities to Antibiotics.

Objectives: Coagulase-negative staphylococci (CNS) are commensal skin microbiota but may also cause septicemia, endocarditis, and systemic infections. Staphylococcus lugdunensis, is a member of CNS, but their antibiotic susceptibility test should be evaluated as Staphylococcus aureus not as CNS. We aimed to investigate S.lugdunensis and selected CNS strains by simple biochemical method and determination of their susceptibilities to antibiotics. Methods: A total of 251 CNS isolates were collected from blood culture bottles sent to Istanbul Faculty of Medicine Department of Medical Microbiology, between 2018 and 2019. PYR (pyrrolidonyl arylamidase) and ODC (ornithine decarboxylase) tests were performed on total of CNS isolates and API Staph was used for identification of the isolates giving positive result in both or either of these two tests. Disk diffusion method was used for the determination of antibiotic susceptibility of the isolates. S. aureus ATCC 25923 and S S.lugdunensis ATCC® 49576 strains were used as quality control strains in disc diffusion method, and biochemical tests, respectively. Results: Twenty three out of 251 CNS isolates were positive in each or both of PYR and ODC tests. We detected the first S.lugdunensis isolate from eye vitreous fluid of patient developed a postoperative endophthalmitis in Turkey. This isolate gave dual positive with ODC, PYR, and API Staph. Other 22 CNS isolates were from blood cultures and distributed as follows; 14 Staphylococcus haemolyticus and three Staphylococcus chromogenes isolates were PYR positive and ODC negative and five Staphylococcus epidermidis isolates were ODC positive and PYR negative. All isolates except S.lugdunensis were resistant to penicillin (95.7%) and 20 (87.0%) isolates were found to be methicillin resistant. Conclusions: ODC and PYR are cost effective tests and easily applicable for accurate identification of S.lugdunensis, and eliminating of opportinistic pathogens such as S. epidermidis, S. haemolyticus, and S. chromogenes from other CNS species in postoperative endophthalmitis and pateints with malignancies. Linezolid was very effective (100%) on four selected CNS species.

Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy.

Treatment of patients with triple-negative breast cancer (TNBC) is limited by a lack of effective molecular therapies targeting this disease. Recent studies have identified metabolic alterations in cancer cells that can be targeted to improve responses to standard-of-care chemotherapy regimens. Using MDA-MB-468 and SUM-159PT TNBC cells, along with LC-MS/MS and HPLC metabolomics profiling, we found here that exposure of TNBC cells to the cytotoxic chemotherapy drugs cisplatin and doxorubicin alter arginine and polyamine metabolites. This alteration was because of a reduction in the levels and activity of a rate-limiting polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). Using gene silencing and inhibitor treatments, we determined that the reduction in ODC was mediated by its negative regulator antizyme, targeting ODC to the proteasome for degradation. Treatment with the ODC inhibitor difluoromethylornithine (DFMO) sensitized TNBC cells to chemotherapy, but this was not observed in receptor-positive breast cancer cells. Moreover, TNBC cell lines had greater sensitivity to single-agent DFMO, and ODC levels were elevated in TNBC patient samples. The alterations in polyamine metabolism in response to chemotherapy, as well as DFMO-induced preferential sensitization of TNBC cells to chemotherapy, reported here suggest that ODC may be a targetable metabolic vulnerability in TNBC.

Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.

Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.

Reduction of oxidative stress and ornithine decarboxylase expression in a human prostate cancer cell line PC-3 by a combined treatment with α-tocopherol and naringenin.

Differentiation of a human aggressive PC-3 cancer cell line was obtained, in a previous investigation, by the synergic effect of α-tocopherol (α-TOC) and naringenin (NG). This combined treatment induced apoptosis and subsequent reduction of the PC-3 cell proliferation and invasion, by a pro-differentiating action. Since one of the peculiar characteristics of NG and α-TOC is their strong antioxidant activity, this study aimed to investigate their potential effect on the activity of the main enzymes involved in the antioxidant mechanism in prostate cancer cells. NG and α-TOC administered singularly or combined in the PC-3 cell line, affected the activity of several enzymes biomarkers of the cellular antioxidant activity, as well as the concentration of total glutathione (GSH + GSSG) and thiobarbituric acid reactive substances (TBARS). The combined treatment increased the TBARS levels and superoxide dismutase (SOD) activity, while decreased the glutathione S-transferase (GST), glutathione reductase (GR), and glyoxalase I (GI) activities. The results obtained indicate that a combined treatment with these natural compounds mitigated the oxidative stress in the human PC-3 cell line. In addition, a significant reduction of both ornithine decarboxylase (ODC) expression and intracellular levels of polyamines, both well-known positive regulators of cell proliferation, accompanied the reduction of oxidative stress observed in the combined α-TOC and NG treatment. Considering the established role of polyamines in cell differentiation, the synergism with NG makes α-TOC a potential drug for further study on the differentiation therapy in prostate cancer patients.

Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines.

The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation.

SKP2, positively regulated by circ_ODC1/miR-422a axis, promotes the proliferation of retinoblastoma.

Retinoblastoma (RB) is the most common intraocular malignancy in infants and children. S-phase kinase-associated protein 2 (SKP2) has been unmasked as an oncogene in a great many of carcinomas. The biologic function and the detailed molecular mechanism of SKP2 in RB need to be better understood. In this study, real-time quantitative polymerase chain reaction and Western blot showed the ectopic expression of SKP2 in RB tissues and cell lines. Loss of function assays showed the attenuated cell proliferation in RB as a result of SKP2 knockdown. In addition, bioinformatics analysis predicted the interaction between SKP2 and miR-422a. Luciferase reporter assay and Pearson's correlation analysis validated the negative correlation between miR-422a and SKP2. MiR-422a overexpression led to a decline of SKP2 expression and cell growth in RB. The binding capacity between miR-422a and circ_ODC1 was also predicted by bioinformatics analysis. Pearson's correlation analysis and luciferase reporter assay confirmed that circ_ODC1 is negatively correlated with miR-422a. Silencing circ_ODC1 resulted in a rise in miR-422a expression and RB cell growth. Moreover, reduced cell growth was restored by SKP2 overexpression. In a word, SKP2, induced by circ_ODC1 and miR-422a, promotes RB proliferation. Our new findings in this research might expedite the discovery of novel prognostic markers and therapeutic targets of RB.

The regulation of triglyceride storage by ornithine decarboxylase (Odc1) in Drosophila.

Polyamines are low molecular weight, organic cations that play a critical role in many major cellular processes including cell cycle regulation and apoptosis, cellular division, tissue proliferation, and cellular differentiation; however, the functions of polyamines in regulating the storage of metabolic fuels such as triglycerides and glycogen is poorly understood. To address this question, we focused on the Drosophila homolog of ornithine decarboxylase (Odc1), the first rate-limiting enzyme in the synthesis of polyamines. Mutants in Odc1 are lethal, but heterozygotes were viable to adulthood. Odc1 heterozygotes appeared larger than their genetic background control flies and consistent with this observation, weighed more than the controls. However, the increased weight was not due to increased food consumption as heterozygotes ate less than the controls. Interestingly, Odc1 heterozygous flies had augmented triglyceride storage, and this lipid phenotype was due to increased triglyceride storage per cell and an increase in the number of fat cells produced. Odc1 heterozygous flies also displayed increased expression of the lipid synthesis genes fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC), suggesting increased lipid synthesis was the cause of the augmented triglyceride phenotype. These results provide a link between the expression of Odc1 and triglyceride storage suggesting that the polyamine pathway plays a role in regulating lipid metabolism.

Polyamines and related signaling pathways in cancer.

Polyamines are aliphatic compounds with more than two amino groups that play various important roles in human cells. In cancer, polyamine metabolism dysfunction often occurs, and regulatory mechanisms of polyamine. This review summarizes the existing research on the metabolism and transport of polyamines to study the association of oncogenes and related signaling pathways with polyamines in tumor cells. Drugs that regulate enzymes have been developed for cancer treatment, and in the future, more attention should be paid to treatment strategies that simultaneously modulate polyamine metabolism and carcinogenic signaling pathways. In addition, the polyamine pathway is a potential target for cancer chemoprevention. As an irreversible suicide inhibitor of the ornithine decarboxylase (a vital enzyme of polyamine synthesis), Difluoro-methylornithine had been shown to have the chemoprevention effect on cancer. Therefore, we summarized and analyzed the chemoprophylaxis effect of the difluoromethylornithine in this systematic review.

Spermidine Exhibits Protective Effects Against Traumatic Brain Injury.

Traumatic brain injury (TBI) causes permanent neurological and cognitive impairments. Effective pharmacological interventions remain elusive. Spermidine is a polyamine compound found in our body that may play a role in brain development and congenital function. In this study, we aimed to investigate the therapeutic potential of spermidine for TBI. We employed experimental closed head injury (CHI) model to evaluate the protective function of spermidine on brain injury. We assessed the neurobehavioral function recovery using Neurologic Severity Score (NSS) and Morris water maze test. At histological level, we evaluated the improvement on brain edema, brain-blood barrier integrity, and cell apoptosis. We also measured inflammatory cytokines and brain injury biomarkers to monitor the treatment outcomes. Last, we correlated the level of spermidine with CHI animal model and TBI patients with different levels of severity. Spermidine administration post-CHI was found effectively to accelerate NSS improvement and shorten latency in maze test. We observed consistent improvements in brain edema, BBB function, and cell death in spermidine-treated group. Inflammatory cytokines and TBI biomarkers, e.g., S100B, MBP and CFAP were reduced significantly in treatment group. Interestingly, inhibiting spermidine synthesis influenced the neurobehavioral recovery in CHI mice. ODC1, a rate-limiting enzyme for spermidine synthesis, was found lower in CHI mice. Serum level of spermidine was significantly lower in TBI patients with severe pathological scores. Spermidine pathway may carry an endogenous role in pathophysiological process of CHI. For the first time, we demonstrated that administrating spermidine may provide a new treatment for TBI.

Evaluating the immunomodulatory responses of LdODC-derived MHC Class-II restricted peptides against VL.

In a bid to develop a novel immunoprophylactic measure against visceral leishmaniasis (VL), MHC class-II-restricted epitopes of LdODC were identified by reverse vaccinology approach. Five consensus HLA-DRB1*0101-restricted epitopes were screened. The analysis revealed that the set of epitopes was presented by at least 54 diverse MHC class-II alleles. Based on in silico screening, followed by molecular dynamics simulation, population coverage analysis, and HLA cross-presentation ability, five best epitopes were evaluated. PBMCs isolated from treated VL subjects, when stimulated with synthetic peptide alone or as a cocktail of peptides, triggered a secretory IFN-γ, but not the IL-10 level. Support in this notion came from intracellular cytokine level with a considerable up-regulated IFN-γ produced by CD4+ T cells. Also, the enhanced IFN-γ seemed to be augmented with the activation of macrophages with prominent IL-12 production. Therefore, it can be concluded that the screened MHC class-II-restricted epitope hotspots derived from Leishmania ODC can trigger CD4+ T cells, which can skew macrophage functions towards protection. However, a detailed analysis can explore its potentiality as a vaccine candidate.

Esophageal Squamous Cell Carcinoma Is Accompanied by Local and Systemic Changes in L-arginine/NO Pathway.

The L-arginine/NO pathway holds promise as a source of potential therapy target and biomarker; yet, its status and utility in esophageal squamous cell carcinoma (ESCC) is unclear. We aimed at quantifying pathway metabolites in sera from patients with ESCC (n = 61) and benign conditions (n = 62) using LC-QTOF-MS and enzyme expression in esophageal tumors and matched noncancerous samples (n = 40) using real-time PCR with reference to ESCC pathology and circulating immune/inflammatory mediators, quantified using Luminex xMAP technology. ESCC was associated with elevated systemic arginine and asymmetric dimethylarginine. Citrulline decreased and arginine bioavailability increased along with increasing ESCC advancement. Compared to adjacent tissue, tumors overexpressed ODC1, NOS2, PRMT1, and PRMT5 but had downregulated ARG1, ARG2, and DDAH1. Except for markedly higher NOS2 and lower ODC1 in tumors from M1 patients, the pathology-associated changes in enzyme expression were subtle and present also in noncancerous tissue. Both the local enzyme expression level and systemic metabolite concentration were related to circulating inflammatory and immune mediators, particularly those associated with eosinophils and those promoting viability and self-renewal of cancer stem cells. Metabolic reprogramming in ESCC manifests itself by the altered L-arginine/NO pathway. Upregulation of PRMTs in addition to NOS2 and ODC1 and the pathway link with stemness-promoting cytokines warrants further investigation.

Polyamine synthesis as a target of MYC oncogenes.

This paper is in recognition of the 100th birthday of Dr. Herbert Tabor, a true pioneer in the polyamine field for over 70 years, who served as the editor-in-chief of the Journal of Biological Chemistry from 1971 to 2010. We review current knowledge of MYC proteins (c-MYC, MYCN, and MYCL) and focus on ornithine decarboxylase 1 (ODC1), an important bona fide gene target of MYC, which encodes the sentinel, rate-limiting enzyme in polyamine biosynthesis. Although notable advances have been made in designing inhibitors against the "undruggable" MYCs, their downstream targets and pathways are currently the main avenue for therapeutic anticancer interventions. To this end, the MYC-ODC axis presents an attractive target for managing cancers such as neuroblastoma, a pediatric malignancy in which MYCN gene amplification correlates with poor prognosis and high-risk disease. ODC and polyamine levels are often up-regulated and contribute to tumor hyperproliferation, especially of MYC-driven cancers. We therefore had proposed to repurpose α-difluoromethylornithine (DFMO), an FDA-approved, orally available ODC inhibitor, for management of neuroblastoma, and this intervention is now being pursued in several clinical trials. We discuss the regulation of ODC and polyamines, which besides their well-known interactions with DNA and tRNA/rRNA, are involved in regulating RNA transcription and translation, ribosome function, proteasomal degradation, the circadian clock, and immunity, events that are also controlled by MYC proteins.

Volatile Composition and Biological Activities of the Leaf Essential Oil from Zanthoxylum limoncello Grown in Oaxaca, México.

Zanthoxylum limoncello is a native plant from southern Mexico which is used as a timber source, condiment and as a traditional medicine. Herein, we report on the volatile content of the leaf essential oil and its biological activities. The annual essential oils (2015-2018) contained volatile organic compounds which exhibited a moderate growth inhibitory activity against H. pylori ATCC 53504 (MIC 121.4-139.7 µg mL-1 ), 26695 (MIC 85.5-94.9 µg mL-1 ) and J99 (MIC 94.7-110.4 µg mL-1 ). These hydrodistillates contained 2-undecanone (31.6-36.8 %; MIC 185.3-199.2 µg mL-1 ) and 2-undecenal (25.1-35.7 %; MIC 144.8-111.3 µg mL-1 ) as the most abundant compounds which were partially involved in the anti-H. pylori activity. The human ornithine decarboxylase enzyme (ODC1), which shows increased activity in several cancer types, was non-competitively inhibited (Vmax 2.7>0.8 Kcat s-1 ) by the essential oil of Z. limoncello as well as by 2-undecanone and 2-undecenal in accordance to in vitro kinetic studies. In silico calculations strongly suggest that the carbonyl group of these oxygenated hydrocarbons interacts with both Asn319 and Ala39 at the subunit A of ODC1. Considering that Ala39 is located close to Asn44, a crucial amino acid of the ODC's allosteric site, the non-competitive inhibition of the enzyme by 2-undecanone and 2-undecenal is endorsed. Finally, the essential oil of Z. limoncello and its main volatiles showed a significant (p<0.01) and prolonged repellent effect against Aedes aegypti.