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PubMed1993

Effect of one hyperbaric oxygen-induced convulsion on cortical polyamine content in two strains of mice.

In rat striatum, after one hyperbaric oxygen (HBO)-induced convulsion, polyamine changes are found that could promote N-methyl-D-aspartate (NMDA) activation. In the HBO-sensitive CD1 mouse, unlike in the common C57 strain, there is some support for NMDA activation after the HBO seizure. We measured PA cortical content before and after the first HBO-induced convulsion (about 608 kPa O2) in CD1 and C57 strains. Putrescine, spermidine and spermine were dansyl derived and analysed by HPLC. Exposure to HBO significantly increased putrescine content only in CD1 though a similar trend was observed in C57. No further increase was observed after convulsion whatever the strain. There were no significant changes in spermidine or spermine to support NMDA activation. Therefore, putrescine increase in CD1 cortex could reflect the free radical formation that is known to be greater in CD1 than in C57 mouse. Attempts to increase putrescine levels before HBO exposure hastened HBO-induced convulsion, less than spermidine or spermine. Because of physiological polyamine interconversion, additional experiments with indirect manipulation of putrescine levels and study of their time-course would precise these preliminary reports on putrescine and HBO.

Animals↗
PubMed2002

Collagen sandwich culture affects intracellular polyamine levels of human hepatocytes.

Extracellular matrices, like collagen layers, play an important role in preventing dedifferentiation of hepatocytes in long-term culture experiments. It has also been shown that polyamines are crucial for cell growth and liver differentiation - regeneration. Primary cultured hepatocytes with their low mitotic activity might be a valuable tool in studying the role of polyamines in differentiation. Here, our goal was to investigate whether an extracellular cell culture matrix can influence intracellular polyamine levels in human hepatocytes during long-term culture. Primary human hepatocytes were isolated from surgical tissue resections and were maintained either in single collagen (SG) or double collagen gel (DG) layer (sandwich) culture systems. Cell viability and function were examined and intracellular polyamine levels were measured using a highly sensitive high performance liquid chromatography (HPLC) method. Hepatocytes showed high viability in both culture systems used, but albumin secretion was diminished in SG cultured hepatocytes after 14 days. In general, total intracellular polyamine levels of hepatocytes decreased markedly in both SG and DG within the first days of culture, but remained constant until day 21 with a SG/DG ratio of about 1.4. Individual polyamines levels were dependent on the culture time and system, where spermine decreased and putrescine increased in both SG and DG over time (day 14), but spermidine increased only in DG. Our results suggest that polyamine levels, in particular putrescine, might be important regulators of hepatocyte specific function in vitro and therefore serve as a marker of differentiation for cultivated human hepatocytes.

Biogenic Polyamines↗
PubMed2001

Microecology, bacterial vaginosis and probiotics: perspectives for bacteriotherapy.

Probiotics enriched in lactobacilli have been proposed as an effective and alternative tool to antibiotics for the treatment of bacterial vaginosis. The protective role of H(2)O(2)-producing lactobacilli has been strongly emphasized, but no clear-cut correlation appears to link the metabolic characteristics of administered lactobacilli with the clinical impact of probiotic therapy. On account of our review of basic mechanisms involved in bacterial vaginosis, we suggest that lactobacilli with an elevated arginine deiminase activity could have a greater therapeutic potential than strains producing only H(2)O(2). Preliminary results from our laboratory have demonstrated that treatment with probiotics containing arginine deiminase-positive lactobacilli improves clinical symptoms and is paralleled by a significant decline of polyamine levels in vaginal microenvironment. This is of outstanding interest due to the central role of polyamines in the pathogenesis of bacterial vaginosis. We should critically rethink, against this perspective, the use of probiotics for the treatment of affected women.

Anti-Bacterial Agents↗
PubMed2004

MEK1 restores migration of polyamine-depleted cells by retention and activation of Rac1 in the cytoplasm.

We previously showed that polyamines are required for proliferation and migration both in vivo and in a cultured intestinal epithelial cell (IEC-6) model. Wounding of the IEC-6 monolayer induced transient ERK activation, which was further enhanced by EGF. EGF stimulated migration in control and polyamine-depleted cells, but the degree of stimulation was significantly less in polyamine-depleted cells. Inhibition of MEK1 inhibited basal as well as EGF-induced ERK activation and migration. Expression of constitutively active (CA)-MEK and dominant-negative (DN)-MEK had significant effects on F-actin structure. CA-MEK increased stress fiber and lamellipodia formation, while DN-MEK showed loss of stress fibers and abnormal actin cytoskeletal structure. Unlike EGF, CA-MEK significantly increased migration of both control and polyamine-depleted cells. The most important and significant finding in this study was that polyamine depletion caused localization of Rac1 and RhoA to the nuclear as well as perinuclear regions. Interestingly, CA-MEK completely reversed the subcellular distribution of Rac1 and RhoA proteins in polyamine-depleted cells. Polyamine depletion increased Rac1 in the nuclear fraction and decreased it in the cytoplasmic and membrane fractions of vector-transfected cells. CA-MEK prevented accumulation of Rac1 in the nucleus. Polyamine depletion significantly decreased Rac1 activity during 6-h migration in vector-transfected cells. Cells transfected with CA-MEK had almost identical levels of activated Rac1 in all three groups. These results suggest that polyamine depletion prevents activation of Rac1 and RhoA by sequestering them to the nucleus and that expression of constitutively active MEK reverses this effect, creating the cellular localization required for activation.

Animals↗
PubMed1989

Increased polyamines may downregulate interleukin 2 production in rheumatoid arthritis.

Polyamines downregulate immune reactivity. RA is associated with decreased IL 2 production. In this study, we present evidence to suggest that excessive polyamines can contribute to the IL 2 deficiency in RA. Blocking polyamine production with inhibitors of ornithine decarboxylase results in increased IL 2 production by RA PBMC. Moreover, polyamine oxidase (PAO) inhibitors and catalase also increase IL 2 production by RA PBMC. This effect of PAO inhibition is monocyte mediated. After 3 d in culture, RA PBMC produce three times more IL 2 than do normal PBMC. This rise is prevented by exogenous spermidine but only in the presence of monocytes. The concentration of polyamines in RA PBMC and synovial fluid MNC is 2-20-fold higher than in normal cells. Thus, polyamines and their oxidation products downregulate IL 2 production by RA PBMC and may account for the decreased T cell effector function seen in this disease.

Adult↗
PubMed2000

Measurements of macromolecule-bound and ultra-filtrable polyamines in rat liver homogenized without buffer.

Ultra-filtrable and macromolecule-bound polyamines in rat liver homogenates, made without buffer, were determined, using Potter-Elvehjem homogenizer and commercially available, pressure-aided ultrafiltration device with a membrane pore size that allows passage of particles of molecular weight no larger than 5000. About 90% of polyamines in the liver were shown to be equilibrated with externally added 15N-labeled polyamines, based on the difference in the ratio of the natural to 15N-labeled polyamine in the liver homogenate and the ultrafiltrate. The entire amount of ultrafiltrate in the homogenized liver, required for calculation of the amounts of ultra-filtrable and macromolecule-bound polyamines, was estimated to be about 0.25 g in one gram of the homogenate, using a limited dilution curve of spermine in the ultrafiltrate with phosphate buffered saline and distilled water. With this value, ultra-filtrable polyamines in normal rat liver homogenate were calculated as about 25%, 8%, and 2% of the total amount of putrescine, spermidine, and spermine, respectively. The method was then used to measure ultra-filtrable and macromolecule-bound polyamines in regenerating rat liver homogenates, to examine possible changes of polyamines during cell growth. The method was also applied to measure other ultra-filtrable compounds such as amino acids and inorganic ions in rat liver homogenate.

Amino Acids↗
PubMed2006

Suppression of TNF-alpha production by S-adenosylmethionine in human mononuclear leukocytes is not mediated by polyamines.

Endotoxin-induced cytokine production is an important mechanism in the development of several types of liver damage. Methionine, some of its precursors and metabolites were reported to have protective effects against such injury. The aim of this study was to investigate whether methionine, its precursors or metabolites [phosphatidylcholine, choline, betaine, S-adenosylmethionine (SAM)] have a modulating effect on tumor necrosis factor alpha (TNF-alpha) production by endotoxin-stimulated human mononuclear leukocytes and whether SAM-dependent polyamines (spermidine, spermine) are mediators of SAM-induced inhibition of TNF-alpha synthesis. Methionine and betaine had a moderate stimulatory effect on TNF-alpha production, whereas phosphatidylcholine (ID(50) 5.4 mM), SAM (ID(50) 131 microM), spermidine (ID(50) 4.5 microM) and spermine (ID(50) 3.9 microM) had a predominantly inhibitory effect. Putrescine did not alter TNF-alpha release. Inhibitors of polyamine synthesis that blocked either putrescine (difluoromethylornithine) or spermine (CGP48664A) production did not affect TNF-alpha synthesis. Endotoxin stimulation of leukocytes did not alter the intracellular levels of polyamines. In addition, supplementation with SAM did not change the intracellular concentration of either polyamine measured. We conclude that phosphatidylcholine-induced immunosuppression is not caused by methionine and polyamines are not involved in SAM-induced inhibition of TNF-alpha production. The limitation of TNF-alpha release by spermidine is specific and is not due to its conversion into spermine.

Amidines↗
PubMed2001

Polyamines and cell migration.

Leeuwenhoek first described polyamines in 1677, but active investigation did not begin until the 1970's. When intracellular polyamine levels are reduced by inhibitors, mutation, or transfection, severe reductions occur in cell division, cell differentiation, and cell migration. These effects are not difficult to demonstrate and measure, and all can be prevented if supplemental exogenous polyamines are supplied. However, linking the overall effects to molecular events remains to be accomplished. In this review, we discuss work (mostly from the last 10 years) that relates to cell migration. Specifically, we have discussed the biology and biochemistry of the polyamines, their transport and regulation, the structure of the cytoskeleton and the mechanics of cell movement. We have also considered four specific processes that polyamines participate in that may affect cell migration significantly. These are: 1) the regulation of intracellular Ca++ concentration by voltage-gated K+ channels, 2) the maintenance of normal RhoA levels that, with Rac, regulate the assembly of actin stress fibers, focal adhesions, and contractility, 3) the formation of ATP-Mg++-polyamine trimers that enhance the phosphorylation activity of ATP toward enzymes in specific signaling pathways and, 4) alterations in the structure of RNA that change translation initiation sites and affect the expression of proteins.

Animals↗
PubMedDate not supplied

[Role of the energy status and putrescine transport in the maintenance of the intracellular pH homeostasis in the course of alkaline and acidic shifts in Escherichia coli].

Alkaline and acidic shifts in exponentially grown Escherichia coli cultures were accompanied by an abatement of the cell energetic status (decline of ATP and energy charge and increase of the ADP and AMP pools). This event led to a suspension of the growth at (the means of) pH 9.0 and 6.0 accordingly. An increment of ornithine decarboxylase activity and an efflux of putrescine from the cells were observed in the course of alkaline shift. Environmental acidification was accompanied by intensification of the cell respiration rate and H+ATPase activity in the absence of the putrescine efflux from the cells. The involvement of the polyamine synthesizing system in the regulation of cell K+ content and the role of the primary proton pumps in the maintenance of pH homeostasis are discussed.

Acid-Base Equilibrium↗
PubMed1988

Alterations in human circulating and bone marrow mononuclear cell polyamine levels in hematologic malignancies as a consequence of difluoromethylornithine administration.

The effect of administering increasing intravenous doses of difluoromethylornithine on human tumor cell polyamine levels was determined in patients with hematologic malignancies. Difluoromethylornithine from 5.5. to 64 gm/m2 per day was administered to nine patients with refractory acute leukemia or multiple myeloma. Putrescine, spermidine, and spermine levels were determined on a daily basis in the circulating mononuclear cells and on a weekly basis in the mononuclear cells of the bone marrow. Tumor cell putrescine levels declined in 5 patients, spermidine levels declined in 4 patients, and spermine levels declined in 3 patients. Alterations in the polyamine levels of the bone marrow mononuclear cells paralleled those occurring in the peripheral blood mononuclear cells in the patients with leukemia. Seven to ten days of DFMO treatment were required for mononuclear cell polyamine levels to decrease. The higher drug doses were not significantly more effective than the lower doses in bringing about a decline in tumor cell polyamine levels, either with respect to treatment time required for onset of response or with respect to the ultimate extent of response.

Adolescent↗
PubMed1999

Polyamine regulation of plasma membrane phospholipid flip-flop during apoptosis.

During apoptosis, phosphatidylserine (PS) is moved from the plasma membrane inner leaflet to the outer leaflet where it triggers recognition and phagocytosis of the apoptotic cell. Although the mechanisms of PS appearance during apoptosis are not well understood, it is thought that declining activity of the aminophospholipid translocase and calcium-mediated, nonspecific flip-flop of phospholipids play a role. As previous studies in the erythrocyte ghost have shown that polyamines can alter flip-flop of phospholipids, we asked whether alterations in cellular polyamines in intact cells undergoing apoptosis would affect PS appearance, either by altering aminophospholipid translocase activity or phospholipid flip-flop. Cells of the human leukemic cell line, HL-60, were incubated with or without the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), and induced to undergo apoptosis by ultraviolet irradiation. Whereas DFMO treatment resulted in profound depletion of putrescine and spermidine (but not spermine), it had no effect on caspase activity, DNA fragmentation, or plasma membrane vesiculation, typical characteristics of apoptosis. Notably, DFMO treatment prior to ultraviolet irradiation did not alter the decline in PS inward movement by the aminophospholipid translocase as measured by the uptake of 6-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminocaproyl] (NBD)-labeled PS detected in the flow cytometer. Conversely, the appearance of endogenous PS in the plasma membrane outer leaflet detected with fluorescein isothiocyanate-labeled annexin V and enhanced phospholipid flip-flop detected by the uptake of 1-palmitoyl-1-[6-[(7-nitro-2-1, 3-benzoxadiazol-4-yl)aminocaproyl]-sn-glycero-3-phosphocholine (NBD-PC) seen during apoptosis were significantly inhibited by prior DFMO treatment. Importantly, replenishment of spermidine, by treatment with exogenous putrescine to bypass the metabolic blockade by DFMO, restored both enhanced phospholipid flip-flop and appearance of PS during apoptosis. Such restoration was seen even in the presence of cycloheximide but was not seen when polyamines were added externally just prior to assay. Taken together, these data show that intracellular polyamines can modulate PS appearance resulting from nonspecific flip-flop of phospholipids across the plasma membrane during apoptosis.

Apoptosis↗
PubMed2003

Polyamines in cultured rabbit corneal cells.

PURPOSE: To determine whether polyamines are present in corneal cells, whether corneal cell polyamines can be depleted by blocking the first rate-limiting enzyme in the polyamine synthesis pathway, ornithine decarboxylase (ODC), and whether polyamines are required for proliferation in all three corneal cell types. METHODS: Cultured corneal epithelial cells, keratocytes, and endothelial cells were exposed to the specific ODC blocker difluoromethylornithine (DFMO), and ODC activity, intracellular polyamine concentrations, and cell proliferation were measured. RESULTS: DFMO blocked ODC activity in a dose- and time-dependent manner in all three cell types. DFMO treatment completely depleted putrescine and spermidine by 2 days and also significantly depleted spermine. DFMO treatment also inhibited cell growth in all three cell types and this inhibition could be completely reversed by adding exogenous putrescine to the culture medium. CONCLUSIONS: Polyamines are present in all cell types of the cornea, their formation is catalyzed at least in part by ODC, and they are an important component of corneal cell proliferation.

Animals↗
PubMed2002

Effect of polyamine depletion on cone photoreceptors of the developing rabbit retina.

PURPOSE: To measure the concentrations of polyamines, determine their cellular and subcellular localization, and analyze effects of their depletion in developing rabbit retina. METHODS: Isolated retinas at different developmental stages were analyzed for polyamine content by high-performance liquid chromatography (HPLC). An antibody against polyamines was used to localize endogenous stores in both freshly harvested retinas and neonatal retinal explants. To determine the effects of polyamine depletion on immature retina, neonatal explants were cultured in the presence or absence of alpha-difluoromethylornithine (DFMO), an inhibitor of the polyamine synthetic enzyme ornithine decarboxylase (ODC). Similar studies were also performed on dissociated cell cultures. Tissue was assessed using standard histologic stains as well as cell-specific markers (peanut agglutinin for cone photoreceptors and calbindin for horizontal cells). RESULTS: Retinal polyamine content was highest at birth, remained relatively high during the first postnatal week, and then steadily decreased to adult levels. At all ages analyzed, spermine concentration was higher than putrescine or spermidine; however, the differential was greatest in the adult. Polyamine immunoreactivity was localized to distal processes of both rods and cones during development. Strong immunoreactivity was maintained in adult cone inner and outer segments; comparatively weak staining was observed in the adult rods. Heavy staining of ganglion cells was present throughout development but was localized in the cytoplasm in immature cells and in the nucleus in the adult. Amacrine cells stained only in the adult. Polyamine depletion caused a disruption of immature cones, evident in the loss of their somata in the outer nuclear layer, in their processes in the outer plexiform layer in retinal explants, and in their decreased association with horizontal cells in dissociated cell culture. CONCLUSIONS: The relatively high concentrations of polyamines in neonatal retina and their discrete localization in developing photoreceptor outer segments and ganglion cells suggests an important role for these compounds in development. The disruption of cone-specific markers in polyamine-depleted retinas indicates a specific reliance on polyamines for expression of normal cone morphology or morphologic development. These developmental effects may involve polyamine-sensitive ion channels, which are known to exist in retina, or direct interactions with specialized cytoskeletal elements within outer segments.

Aging↗
PubMedDate not supplied

[The mechanisms of nitric oxide production from exogenous and endogenous NO-donating compounds and its effect on deoxyribonucleotide and DNA synthesis].

The mechanisms of exogenous nitric oxide (NO) production through in vivo biotransformation of nitro-, nitroso- and amino-containing substances were discussed. In addition, the mechanisms of production and cellular sources of endogenous NO, appearing in the blood and tissues after the exposure to various DNA-damaging factors, have been considered. Considerable quantities of endogenous NO were detected in the body in the first hours after translation inhibition by cycloheximide or animal exposure to superlethal radiation doses, i.e., after the exposure to factors inducing destructive processes. The time and dose dependences of exogenous and endogenous NO production have been established. NO produced after a single or repeated administration of NO-donating compounds as well as endogenous NO proved to inhibit deoxyribonucleotide (dNTP) and DNA synthesis in animal tissues. Nonspecific compensatory responses to disturbed protein homeostasis included cyclic production of endogenous NO. The maximum levels of nitrosyl complexes were registered when the rate of protein synthesis decreased. The role of polyamines in the induction of macromolecule biosynthesis is discussed and NO production from these arginine-rich compounds is proposed. NO is released at the stage of polyamine inactivation. The inactivation mechanism includes the hydroxylation of aminogroups by NO synthase, the formation of nitroso intermediates, and their denitrosation with NO release.

Animals↗
PubMed1998

Structural specificity of polyamines and polyamine analogues in the protection of DNA from strand breaks induced by reactive oxygen species.

Reactive oxygen species are known to induce strand breaks and/or base modifications in DNA. DNA strand breaks are associated with many pathologies and programmed cell death. We have examined the ability of the polyamines and their analogues to protect phi X-174 plasmid DNA from strand breakage induced by a oxygen-radical generating system. Spermine and several unsymmetrically substituted polyamine analogues reduced the amount of strand breakage at a physiologically relevant concentration of 1 mM. However, putrescine, spermidine, N1-acetylspermine, N1-acetylspermidine and symmetrically alkylated polyamine analogues were not able to reduce strand breakage at the same concentration. Thus, the unsymmetrically alkylated polyamine analogues and natural spermine can protect DNA against strand breakage induced by Cu(II)/H2O2 generated ROS similar to other more classical antioxidants.

Antineoplastic Agents↗
PubMed2004

Effects of polyamines on mitochondrial Ca(2+) transport.

Mammalian mitochondria are able to enhance Ca(2+) accumulation in the presence of polyamines by activating the saturable systems of Ca(2+) inward transport and buffering extramitochondrial Ca(2+) concentrations to levels similar to those in the cytosol of resting cells. This effect renders them responsive to regulate free Ca(2+) concentrations in the physioloical range. The mechanism involved is due to a rise in the affinity of the Ca(2+) transport system, induced by polyamines, most probably exhibiting allosteric behaviour. The regulatory site of this mechanism is the so-called S(1) binding site of polyamines, which operates in physiological conditions and is located in the energy well between the two peaks present in the energy profile of mitochondrial spermine transport. Spermine is bidirectionally transported across teh inner membrane by cycling, in which influx and efflux are driven by electrical and pH gradients, respectively. Most probably, polyamine affects the Ca(2+) transport system when it acts from the outside-that is, in the direction of its uniporter channel, in order to reach the S(1) site. Important physiological functions are related to activation of Ca(2+) transport systems by polyamines and their interactions with the S(1) site. These functions include a rise in the metabolic rate for energy supply and modulation of mitochondrial permeability transition induction, with consequent effects on the triggering of the apoptotic pathway.

Animals↗
PubMed2005

Polyamine transport in parasites: a potential target for new antiparasitic drug development.

The metabolism of the naturally occurring polyamines-putrescine, spermidine and spermine-is a highly integrated system involving biosynthesis, uptake, degradation and interconversion. Metabolic differences in polyamine metabolism have long been considered to be a potential target to arrest proliferative processes ranging from cancer to microbial and parasitic diseases. Despite the early success of polyamine inhibitors such as alpha-difluoromethylornithine (DFMO) in treating the latter stages of African sleeping sickness, in which the central nervous system is affected, they proved to be ineffective in checking other major diseases caused by parasitic protozoa, such as Chagas' disease, leishmaniasis or malaria. In the use and design of new polyamine-based inhibitors, account must be taken of the presence of up-regulated polyamine transporters in the plasma membrane of the infectious agent that are able to circumvent the effect of the drug by providing the parasite with polyamines from the host. This review contains information on the polyamine requirements and molecular, biochemical and genetic characterization of different transport mechanisms in the parasitic agents responsible for a number of the deadly diseases that afflict underdeveloped and developing countries.

Animals↗
PubMed2004

Polyamines as clinical laboratory tools.

Since their discovery by Antoni van Leeuwenhoek in 1678 until the recent development of transgenic mice expressing proteins altering polyamine levels in a tissue-specific manner, polyamines have been the object of intense research efforts which have shed light on several biological and pathological processes. From the discovery of a particular form of proteasome regulation of the catabolism of the key regulatory enzyme in their synthetic pathway, to the experimental cancer treatment or prevention with polyamine antagonists or inhibitors of the latter enzyme, a whole spectrum of interests can be revealed. Still, many aspects of their functions remain elusive and difficulties inherent in their analysis, which relies on sophisticated high-performance liquid chromatographic (HPLC) methods, and the lack of standardization; have hampered the transit from the research realm to the standard clinical laboratory domain. Their assay in biological fluids has been used for cancer diagnosis and for monitoring anticancer treatment. In this article, we attempt to provide an overview of polyamine structure, nutritional value, metabolism, and physiological roles. Next, we will summarize the main analytical methods on which we count, and finally we will address their role in diagnosis of cancer as well their proposed role as antioxidant and antiglycation agents.

Biogenic Polyamines↗