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PubMed2003

Reinvigoration of Pinus radiata is associated with partial recovery of juvenile-like polyamine concentrations.

Polyamine concentrations in consecutive radiata pine (Pinus radiata D. Don) grafts of 30-year-old trees on 1-year-old seedling rootstocks were analyzed by high performance liquid chromatography coupled with fluorescence detection to determine whether reinvigoration is associated with the recovery of polyamine concentrations typical of those in juvenile tissues. Reinvigoration of radiata pine was correlated with the attainment of some, but not all, polyamines characteristic of juvenile trees. In response to reinvigoration, free putrescine, the ratio of free polyamines to low molecular weight polyamine conjugates, and the relative content of putrescine versus spermidine plus spermine increased to values approaching those characteristic of juvenile tissue. In contrast, there was no noticeable change in the concentrations of low molecular weight polyamine conjugates during reinvigoration even though these conjugates increased greatly during tree maturation. We conclude that certain polyamines defined as reinvigoration markers can be used in forestry upgrading programs to assess the morphogenic ability of reinvigorated trees.

Biogenic Polyamines↗
PubMed1990

Polyamine concentrations in pancreatic tissue, serum, and urine of patients with pancreatic cancer.

We investigated the total, free, and acetylated polyamine concentrations in pancreatic tissue, serum, and urine of 20 patients with pancreatic cancer, 30 healthy volunteers, and 40 patients with nonmalignant, gastrointestinal diseases by reversed-phase liquid chromatography. Tissue concentrations in carcinoma compared to histologically unaffected pancreas were significantly higher for putrescine, elevated for cadaverine, and nearly identical for spermidine and spermine, while N1-acetylspermidine was detectable in cancer tissue only. With the exception of free spermine in urine and total spermine in serum, all other polyamines were significantly elevated in the urine and serum of cancer patients compared to healthy controls. These data support the concept that polyamines play an important role in rapidly growing tissues. However, nonmalignant gastrointestinal diseases partly showed similar elevations. Because of this low specificity, polyamines are of little value only as diagnostic markers of pancreatic carcinoma. Since polyamine concentrations normalized in patients after curative operation while they were further elevated in patients with tumor relapse or metastases, polyamines might play a clinical role in predicting therapeutic success or indicating relapse of the tumor. A significant linear correlation of polyamine concentrations and the size of the tumor was found while a significant correlation to CEA, CA 19-9, and CA 125 or the presence of organ metastases did not exist.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed2001

Polyamines in the human gut.

Intracellular polyamine concentrations are maintained by endogenous synthesis and uptake of exogenous polyamines from the gastrointestinal lumen. Recently, much attention has been focused on the role of polyamines in tumour pathogenesis and the possible therapeutic value of reducing polyamine concentrations in tumour tissue. Unfortunately, polyamines also appear to be essential for the maintenance of normal gastrointestinal structure and function. The immediate analytical challenge is to make progress in laboratory methods for polyamine class analyses and assessment of polyamine metabolism. An obvious gastroenterological target is to make up for past neglect of the function of these important dietary components.

Digestive System↗
PubMed1983

Decreased urinary polyamines in patients with psoriasis treated with etretinate.

Oral administration of the aromatic retinoid etretinate is effective therapy for psoriasis and other epidermal hyperproliferative disorders. Since polyamine metabolism is known to be important in cell growth and differentiation, we measured urinary levels of the polyamines putrescine, spermidine, and spermine as a reflection of cutaneous polyamine metabolism in 19 psoriatic patients treated with etretinate for 16 weeks. Using thin-layer chromatography, polyamine determinations were performed on urine collected pretherapy, during therapy, and 8 weeks after therapy was concluded. Good to excellent clearing of psoriasis occurred in 18 of 19 patients. All urinary polyamines showed a downward trend in the first week of therapy, prior to significant clinical improvement. At week 16 of therapy, the greatest reduction in mean urinary polyamine content occurred. Mean putrescine levels decreased from pretherapy to week 16 by 27% (p less than 0.001), mean spermidine values fell by 34% (p less than 0.001), and mean spermine levels declined by 37% (p = 0.005). These data are consistent with the hypothesis that etretinate inhibits polyamine biosynthesis.

Adult↗
PubMed2004

The influence of Lactobacillus brevis on ornithine decarboxylase activity and polyamine profiles in Helicobacter pylori-infected gastric mucosa.

BACKGROUND: Functional probiotics may prevent Helicobacter pylori infection, and some evidence suggests that they also possess antitumor properties. Lactobacillus brevis (CD2) is a functional Lactobacillus strain with peculiar biochemical features, essentially related to the activity of arginine deiminase. This enzyme catalyzes the catabolism of arginine and affects the biosynthesis of polyamines (putrescine, spermidine, and spermine). Polyamines are polycations found in high concentrations in both normal and neoplastic cells. Our aims were: 1, to assess whether oral administration of L. brevis (CD2) affects H. pylori survival in the human gastric mucosa; 2, to evaluate the effects of L. brevis (CD2) on polyamine biosynthesis in gastric biopsies from H. pylori-positive patients. MATERIALS AND METHODS: For 3 weeks before endoscopy, 22 H. pylori-positive dyspeptic patients randomly received (ratio 1 : 1) high oral doses of L. brevis (CD2) or placebo. Before and after treatment, H. pylori infection was determined by urea breath test (UBT). In gastric biopsies, ornithine decarboxylase activity and polyamine levels were, respectively, evaluated by a radiometric technique and high-pressure liquid chromatography (HPLC). RESULTS: L. brevis (CD2) treatment did not eradicate H. pylori. However, a reduction in the UBT delta values occurred, suggesting a decrease in intragastric bacterial load. Significantly, L. brevis (CD2) induced a decrease in gastric ornithine decarboxylase activity and polyamine levels. CONCLUSIONS: Our data support the hypothesis that L. brevis (CD2) treatment decreases H. pylori colonization, thus reducing polyamine biosynthesis. Alternatively, the arginine deiminase activity following L. brevis (CD2) administration might cause arginine deficiency, preventing polyamine generation from gastric cells.

Adult↗
PubMed2004

Amelioration in secretion of hyperthermostable and Ca2+ -independent alpha-amylase of Geobacillus thermoleovorans by some polyamines and their biosynthesis inhibitor methylglyoxal-bis-guanylhydrazone.

AIM: Effect of polyamines and their biosynthesis inhibitors on the production of hyperthermostable and Ca2+ -independent alpha-amylase by Geobacillus thermoleovorans MTCC 4220. METHODS AND RESULTS: The alpha-amylase was produced in starch-yeast extract-tryptone (SYT) broth with different polyamines (PA) and polyamine biosynthesis inhibitors, methylglyoxal-bis-guanylhydrazone (MGBG) and cyclohexylammonium sulphate (CHA) at 70 degrees C. The bacterial pellets were obtained after growing G. thermoleovorans at different temperatures, and used in determining total PA. The cell-free culture filtrates were used in alpha-amylase assays. During growth, total polyamines in biomass increased till 2 h, and thereafter, decreased gradually. The total polyamine content was very high in the biomass cultivated at 55 degrees C when compared with that of higher temperatures. Enzyme titre enhanced up to 70 degrees C, and thereafter declined. Extracellular enzyme and protein levels declined in the presence of exogenously added PA. The intracellular enzyme titres, however, were higher in putrescine (put) and spermidine (spd) than in spermine (spm). Polyamine biosynthesis inhibitor, MGBG enhanced secretion of alpha-amylase in a laboratory fermentor as well as shake flasks, although CHA did not affect it. CONCLUSIONS: The intracellular accumulation of put in the presence of MGBG appeared to enhance synthesis and secretion of alpha-amylase. Extracellular enzyme and protein levels were low in the presence of exogenously added PA, but their intracellular levels, however, were higher in put and spd than in spm. SIGNIFICANCE AND IMPACT OF THE STUDY: A substantial increase in the synthesis and secretion of alpha-amylase was attained in G. thermoleovorans in the presence of polyamine biosynthesis inhibitor MGBG.

Bacillus↗
PubMed1990

Effect of polyamines on the activity of malarial alpha-like DNA polymerase.

DNA polymerase from the malarial parasite Plasmodium falciparum required Mg2+ for activity, Putrescine (1 mM) caused a twofold increase in enzyme activity in the presence of a suboptimal concentration of MgCl2 (2 mM). Spermidine (1.5-2.0 mM) or spermine (0.1-0.3 mM) increased the activity of malarial DNA polymerase, in the presence of 2 mM MgCl2, by factors of 6 and 3-5, respectively. The activity of DNA polymerase from calf thymus or from NIH 3T3 cells transformed by the ras oncogene were not stimulated by these polyamines to the same extent. These findings suggest that in malaria-infected erythrocytes, polyamines, at physiological concentrations, serve as a cofactor for the parasitic alpha-like DNA polymerase. Malarial parasites grown in cultured human erythrocytes did not synthesize DNA after treatment with alpha-difluoromethylornithine, which caused polyamine depletion in the infected cells. DNA synthesis was resumed after adding putrescine to the polyamine-depleted cultures. DNA synthesis was also initiated when actinomycin D was added along with putrescine to polyamine-depleted cells. It thus appears that polyamines are essential for the translation of the DNA polymerase mRNA and that polyamines play an important role in regulating the cell cycle of the malarial parasite.

Animals↗
PubMed1994

The involvement of polyamines in the activation of vitamin D receptor from porcine intestinal mucosa.

In the intracellular process of the action of calcitriol, vitamin D receptor is thought to undergo some kind of physiochemical change, called activation, before the receptor binds to the vitamin D response element of the gene. In this paper, the effects of polyamines and their analogues on the sedimentation properties of vitamin D receptor prepared from porcine intestinal mucosa, and on DNA binding activity of the receptor, were studied. In sucrose density gradient analysis, polyamines decreased the sedimentation coefficient of vitamin D receptor in a dose-dependent fashion. Polyamines increased DNA binding activity of vitamin D receptor dose-dependently. These findings show that polyamines can activate vitamin D receptor in vitro. Among naturally existing polyamines, spermidine and spermine, but not putrescine, were effective within their physiological intracellular concentrations, suggesting that both spermidine and spermine can activate vitamin D receptor in vivo as well. Sucrose density gradient analysis using various kinds of polyamine analogues having various numbers of cations showed that the number of cation of polyamines is important for the efficiency to change the sedimentation coefficient of vitamin D receptor, and that the distance between two cationic charges does not play an important role.

Animals↗
PubMed2004

Genetic approaches to the cellular functions of polyamines in mammals.

The polyamines putrescine, spermidine and spermine are organic cations shown to participate in a bewildering number of cellular reactions, yet their exact functions in intermediary metabolism and specific interactions with cellular components remain largely elusive. Pharmacological interventions have demonstrated convincingly that a steady supply of these compounds is a prerequisite for cell proliferation to occur. The last decade has witnessed the appearance of a substantial number of studies, in which genetic engineering of polyamine metabolism in transgenic rodents has been employed to unravel their cellular functions. Transgenic activation of polyamine biosynthesis through an overexpression of their biosynthetic enzymes has assigned specific roles for these compounds in spermatogenesis, skin physiology, promotion of tumorigenesis and organ hypertrophy as well as neuronal protection. Transgenic activation of polyamine catabolism not only profoundly disturbs polyamine homeostasis in most tissues, but also creates a complex phenotype affecting skin, female fertility, fat depots, pancreatic integrity and regenerative growth. Transgenic expression of ornithine decarboxylase antizyme has suggested that this unique protein may act as a general tumor suppressor. Homozygous deficiency of the key biosynthetic enzymes of the polyamines, ornithine and S-adenosylmethionine decarboxylase, as achieved through targeted disruption of their genes, is not compatible with murine embryogenesis. Finally, the first reports of human diseases apparently caused by mutations or rearrangements of the genes involved in polyamine metabolism have appeared.

Acetyltransferases↗
PubMed1991

Complex interactions between polyamines and calpain-mediated proteolysis in rat brain.

Polyamine synthesis is induced by various extracellular signals, and it is widely held that this biochemical response participates in cell growth and differentiation. Certain of the triggers for synthesis in brain tissues also increase the breakdown of high-molecular-weight structural proteins, apparently by activating calcium-dependent proteases (calpains). The present experiments tested the possibility that calpain activity is modulated by polyamines. Spermine, spermidine, and putrescine all increased calcium-dependent proteolysis of [14C]casein by soluble fractions of rat brain. The order of potency was spermine greater than spermidine greater than putrescine, with apparent affinities of 30, 300, and 6,000 microM, respectively. Each of the three polyamines at physiological concentrations also potentiated the calcium-dependent breakdown of two endogenous high-molecular-weight structural proteins known to be substrates of calpain, in both supernatant and membrane fractions. The thiol protease inhibitor leupeptin, a known calpain inhibitor, also inhibited calcium-dependent proteolysis in the presence and absence of polyamines. The polyamines did not increase the activity of purified calpain I or calpain II determined with either [14C]casein or purified spectrin as the substrate, nor did they interfere with the inhibitory effects of calpastatin, an endogenous inhibitor of calpain. However, polyamines potentiated the stimulation of endogenous but not purified calpain activity produced by an endogenous calpain activator. These results suggest a role for polyamines in protein degradation as well as protein synthesis.

Animals↗
PubMedDate not supplied

Mice with targeted disruption of spermidine/spermine N1-acetyltransferase gene maintain nearly normal tissue polyamine homeostasis but show signs of insulin resistance upon aging.

The N(1)-acetylation of spermidine or spermine by spermidine/spermine N(1)-acetyltransferase (SSAT) is the ratecontrolling enzymatic step in the polyamine catabolism. We have now generated SSAT knockout (SSAT-KO) mice, which confirmed our earlier results with SSATdeficient embryonic stem (ES) cells showing only slightly affected polyamine homeostasis, mainly manifested as an elevated molar ratio of spermidine to spermine in most tissues indicating the indispensability of SSAT for the spermidine backconversion. Contrary to SSAT deficient ES cells, polyamine pools in SSAT-KO mice remained almost unchanged in response to N(1),N(11)-diethylnorspermine (DENSPM) treatment compared to a significant reduction of the polyamine pools in the wild-type animals and ES cells. Furthermore, SSATKO mice were more sensitive to the toxicity exerted by DENSPM in comparison with wild-type mice. The latter finding indicates that inducible SSAT plays an essential role in vivo in DENSPM treatmentevoked polyamine depletion, but a controversial role in toxicity of DENSPM. Surprisingly, liver polyamine pools were depleted similarly in wild-type and SSAT-KO mice in response to carbon tetrachloride treatment. Further characterization of SSAT knockout mice revealed insulin resistance at old age which supported the role of polyamine catabolism in glucose metabolism detected earlier with our SSAT overexpressing mice displaying enhanced basal metabolic rate, high insulin sensitivity and improved glucose tolerance. Therefore SSAT knockout mice might serve as a novel mouse model for type 2 diabetes.

Acetyltransferases↗
PubMed1990

Polyamine analysis of infected root canal contents related to clinical symptoms.

The contents of infected root canals were collected by mechanical and chemical debridement. Intracanal polyamines were identified and quantified by HPLC in all canals examined, however, no histamine was detected in any canal. The relationship between the amount of each polyamine and clinical signs of the teeth was analyzed statistically. The teeth without clinical signs tended to have limited varieties and smaller amounts of polyamines. Using chi 2, the amounts were significantly greater in teeth with spontaneous pain, swelling and putrescent odor (p less than 0.01), with exudate (p less than 0.025) and with percussion pain (p less than 0.1) than in teeth without. Amounts of putrescine (p less than 0.05) and total polyamines (p less than 0.01) were greater in teeth with spontaneous pain and percussion pain than in teeth without clinical sign, and those with root canal exudate also had greater amounts of total polyamines than those without (p less than 0.01). The amounts of cadaverine, however, from the teeth with gingival fistulae, was greater than from those without (p less than 0.05). No significant relationship was established between the amount of each polyamine and the presence of putrescent odor or gingival swelling. Intracanal polyamines, especially putrescine may leak out through apical foramen and may be implicated in pain production by eliciting acute inflammatory response in the periapical tissues.

Adolescent↗
PubMed1984

Polyamine oxidase-mediated intraerythrocytic killing of Plasmodium falciparum: evidence against the role of reactive oxygen metabolites.

The polyamines spermine and spermidine, in the presence of polyamine oxidase, were shown to be cytotoxic in vitro to various isolates of Plasmodium falciparum. Neither polyamines nor polyamine oxidase alone was cytotoxic. This cytotoxicity was manifested by the degeneration of the parasites into crisis forms and by the inhibition of methionine incorporation by the parasites. Only 2 to 2.5 h of exposure to the reaction mixture (polyamine oxidase, 100 micrograms/ml; spermine, 1 mM) resulted in parasite death. It was shown that ammonia, hydrogen peroxide, and associated reactive oxygen intermediates produced during the oxidation of polyamines were not the cause of the parasite death observed in this system. This suggested that aldehydes or further breakdown products of these, e.g., acrolein (or both), need to be considered as the effector substances of the polyamine oxidase-mediated killing of P. falciparum.

Animals↗
PubMed1973

Stable ribonucleic acid synthesis in stringent (rel+) and relaxed (rel-) polyamine auxotrophs of Escherichia coli K-12.

The relationship of polyamines to stable ribonucleic acid (RNA) synthesis under conditions of amino acid withdrawal or chloramphenicol treatment was examined with the use of a closely related rel(+), rel(-) pair conditionally incapable of synthesizing putrescine. Under conditions of polyamine starvation, the cellular sperimidine level fell to one-third to one-half of the value observed in putrescine-supplemented cultures and putrescine became undetectable; cadaverine was synthesized by both strains, but the relaxed strain, MA 252, accumulated less cadaverine per cell than its stringent twin, MA 254. Upon amino acid withdrawal, the stringent strain remained stringent whether starved of or supplemented with polyamines. Similarly, the relaxed strain was capable of making RNA either with or without polyamine starvation. On the addition of chloramphenicol or upon amino acid withdrawal in the relaxed strain, supplementation with spermidine had no effect on the initial rate of RNA synthesis, although RNA accumulation was greater in the presence of added spermidine. Spermidine added at the conclusion of RNA synthesis prompted additional synthesis, although preincubation with spermidine again had no effect on the initial rate. All forms of stable RNA species were made with polyamine supplementation. The present data appear to rule out the possibility that polyamines are primary causative agents in stimulating RNA synthesis, but rather suggest an indirect or secondary role for spermidine in which the polyamines "stimulate" stable RNA synthesis probably by relieving RNA product inhibition of RNA synthesis.

Amino Acids↗
PubMed1995

Polyamines as targets for therapeutic intervention.

Polyamines are ubiquitous cell components essential for normal growth. Compounds interfering with polyamine biosynthesis or function have considerable potential for use as therapeutic agents. Inhibitors of ornithine decarboxylase have been shown to be valuable for the treatment of diseases caused by parasitic protozoa, most notably African sleeping sickness. They may also be useful chemopreventive and antineoplastic agents. Inhibitors of S-adenosylmethionine decarboxylase also have potential as treatments of these diseases. Protocols minimizing uptake of exogenous polyamines via the polyamine-transport system will probably be needed for the full potential of the inhibitors to be realized. Polyamine analogues, notably those with ethyl or benzyl groups on the terminal nitrogen atoms, have potent antiproliferative activity and are promising agents for the treatment of cancer. These analogues are transported by the polyamine-transport system, and their therapeutic effects are less likely to be blocked by the availability of the exogenous polyamines.

Adenosylmethionine Decarboxylase↗
PubMed2006

Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest.

Expression of spermidine/spermine N(1)-acetyltransferase (SSAT) increases in kidneys subjected to ischemia-reperfusion injury (IRI). Increased expression of SSAT in vitro leads to alterations in cellular polyamine content, depletion of cofactors and precursors of polyamine synthesis, and reduced cell proliferation. In our model system, a >28-fold increase in SSAT levels in HEK-293 cells leads to depletion of polyamines and elevation in the enzymatic activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase, suggestive of a compensatory reaction to increased polyamine catabolism. Increased expression of SSAT also led to DNA damage and G(2) arrest. The increased DNA damage was primarily due to the depletion of polyamines. Other factors such as increased production of H(2)O(2) due to polyamine oxidase activity may play a secondary role in the induction of DNA lesions. In response to DNA damage the ATM/ATR --> Chk1/2 DNA repair and cell cycle checkpoint pathways were activated, mediating the G(2) arrest in SSAT-expressing cells. In addition, the activation of ERK1 and ERK2, which play integral roles in the G(2)/M transition, is impaired in cells expressing SSAT. These results indicate that the disruption of polyamine homeostasis due to enhanced SSAT activity leads to DNA damage and reduced cell proliferation via activation of DNA repair and cell cycle checkpoint and disruption of Raf --> MEK --> ERK pathways. We propose that in kidneys subjected to IRI, one mechanism through which increased expression of SSAT may cause cellular injury and organ damage is through induction of DNA damage and the disruption of cell cycle.

Acetyltransferases↗
PubMed1999

Regulation of intracellular polyamine biosynthesis and transport by NO and cytokines TNF-alpha and IFN-gamma.

Nitric oxide (NO) has been described to exert cytostatic effects on cellular proliferation; however the mechanisms responsible for these effects have yet to be fully resolved. Polyamines, conversely, are required components of cellular proliferation. In experimental models of inflammation, a relationship between these two pathways has been suggested by the temporal regulation of a common precursor, arginine. This study was undertaken to determine the effects NO and the NO synthase (NOS)-inducing cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), exert on polyamine regulation. The transformed kidney proximal tubule cell line, MCT, maintains high constitutive levels of the first polyamine biosynthetic enzyme, ornithine decarboxylase (ODC). NO donors markedly suppressed ODC activity in MCT and all other cell lines examined. TNF-alpha and IFN-gamma induction of NO generation resulted in suppressed ODC activity, an effect prevented by the inducible NOS inhibitor L-N6-(1-iminoethyl)lysine (L-NIL). Dithiothreitol reversal of NO-mediated ODC suppression supports nitrosylation as the mechanism of inactivation. We also evaluated polyamine uptake, inasmuch as inhibition of ODC can result in a compensatory induction of polyamine transporters. Administration of NO donors, or TNF-alpha and IFN-gamma, suppressed [3H]putrescine uptake, thereby preventing transport-mediated reestablishment of intracellular polyamine levels. This study demonstrates the capacity of NO and inflammatory cytokines to regulate both polyamine biosynthesis and transport.

3T3 Cells↗
PubMed2000

Role of K(+) channel expression in polyamine-dependent intestinal epithelial cell migration.

Polyamines are essential for cell migration during early mucosal restitution after wounding in the gastrointestinal tract. Activity of voltage-gated K(+) channels (Kv) controls membrane potential (E(m)) that regulates cytoplasmic free Ca(2+) concentration ([Ca(2+)](cyt)) by governing the driving force for Ca(2+) influx. This study determined whether polyamines are required for the stimulation of cell migration by altering K(+) channel gene expression, E(m), and [Ca(2+)](cyt) in intestinal epithelial cells (IEC-6). The specific inhibitor of polyamine synthesis, alpha-difluoromethylornithine (DFMO, 5 mM), depleted cellular polyamines (putrescine, spermidine, and spermine), selectively inhibited Kv1.1 channel (a delayed-rectifier Kv channel) expression, and resulted in membrane depolarization. Because IEC-6 cells did not express voltage-gated Ca(2+) channels, the depolarized E(m) in DFMO-treated cells decreased [Ca(2+)](cyt) as a result of reduced driving force for Ca(2+) influx through capacitative Ca(2+) entry. Migration was reduced by 80% in the polyamine-deficient cells. Exogenous spermidine not only reversed the effects of DFMO on Kv1.1 channel expression, E(m), and [Ca(2+)](cyt) but also restored cell migration to normal. Removal of extracellular Ca(2+) or blockade of Kv channels (by 4-aminopyridine, 1-5 mM) significantly inhibited normal cell migration and prevented the restoration of cell migration by exogenous spermidine in polyamine-deficient cells. These results suggest that polyamine-dependent intestinal epithelial cell migration may be due partially to an increase of Kv1.1 channel expression. The subsequent membrane hyperpolarization raises [Ca(2+)](cyt) by increasing the driving force (the electrochemical gradient) for Ca(2+) influx and thus stimulates cell migration.

Animals↗