Polyamine metabolism inSetaria cervi,the bovine filarial worm

Spermine and spermidine were found to be the principal polyamines in the bovine filarial parasiteSetaria cervi, whereas putrescine was observed in very low amounts. Studies conducted on the enzymes of polyamine biosynthesis revealed low activity for S-adenosyl-methionine decarboxylase, questionable and negligible activities for the decarboxylation of ornithine and arginine, and appreciable activity for ornithine aminotransferase. Uptake studies with radiolabeled putrescine, spermidine and spermine showed that these amines are rapidly taken up from the medium by an active uptake process. The uptake was temperature-sensitive and abolished at 0–4°C. The questionable presence of biosynthetic enzymes such as ornithine and arginine decarboxylase and, on the other hand, an effective uptake mechanism indicate that the parasite may depend on the host for its polyamine requirement, thereby indicating a possible target for chemotherapy.Communication No. 4114     

Polyamine metabolism during cardiac hypertrophy

Treatment with thyroxine for 7 days to produce myocardial hypertrophy led to an increase in the content of putrescine, spermidine, and spermine in the rat heart. The content of decarboxylated S-adenosylmethionine, the source of the aminopropyl groups needed for polyamine synthesis, was increased by the thyroxine treatment as were the activities of ornithine and S-adenosylmethionine decarboxylases. The enhanced S-adenosylmethionine decarboxylase activity measured in vitro was due to an increase in the amount of enzyme protein as measured by immunotitration with a specific antiserum. In vivo, decarboxylation of S-adenosylmethionine was, therefore, increased both by the increased amount of enzyme protein and by the elevated concentration of putrescine (which activates the enzyme) brought about by the enhanced ornithine carboxylase activity. Spermine synthase did not change significantly during the treatment and spermidine synthase increased only slightly. Therefore, the accumulation of polyamines was mediated predominantly via the increased availability of both putrescine and decarboxylated S-adenosylmethionine. Administration of 1,3-diamino-2-propanol led to a rapid reduction in the activity of ornithine decarboxylase in the heart, and continued exposure to this substance by its inclusion in the drinking water completely prevented the increase in concentration of putrescine and polyamines in response to thyroxine. However, cardiac hypertrophy as measured by the increase in cardiac mass was not prevented by such treatment with 1,3-diaminopropanol, showing that the increased content of polyamines was not essential for the hypertrophic response.     

Polyamine metabolism in muscles of mice and rats

Polyamine biosynthesis in different types of muscle was studied in mice and rats. A sex difference of polyamine biosynthesis in the gastrocnemius of the mouse was demonstrated. Ornithine decarboxylase activity was found to be several-fold higher in the gastrocnemius of the male mouse than in that of the female. Orchiectomy resulted in a decline of enzyme activity in the gastrocnemius. This effect was reversed by the administration of testosterone. The elevation of ornithine decarboxylase activity in the gastrocnemius by testosterone was reflected in an increased content of the polyamines in the muscle. Muscles of other types, i.e. soleus, heart and urinary bladder were shown to be virtually unresponsive to testosterone treatment. Neither were the muscles of the rat, including gastrocnemius, found to be affected by the androgen.     

Polyamine metabolism in rat parotid gland after duct ligation

Parotid ducts were ligated unilaterally in rats for periods from 6 h to 5 months. A slight increase in gland weight was observed during the first 24 h; thereafter, the weight gradually fell, being less than 50% of controls at 5 months. The activity of the putrescine-forming enzyme, ornithine decarboxylase (ODC), increased with peak values by 3 days and 3 weeks. However, the putrescine content had already reached its highest value by 24 h. A notably marked reduction of spermidine and spermine contents was observed by 1 day after ligation and throughout the whole time of observation. The results suggest that an inverse polyamine metabolism occurred, that is, spermine converts to spermidine which in turn converts to putrescine.     

Polyamine metabolism in prostaglandin E2-treated human T lymphocytes

The effects of Prostaglandin (PG) E2 treatment of human T lymphocytes on polyamine metabolism were investigated. PGE2 is known to inhibit lymphocyte proliferation, while polyamines play an important role in several biochemical processes leading to increased cell growth. Preincubation of T lymphocytes with PGE2 (10^-6 M) for 10 min. was able to increase ornithine decarboxylase (ODC) activity and putrescine as well as spermine levels, while spermidine concentration was drastically reduced. After 30 and 60 min of treatment, a decrease in ODC activity and putrescine concentration was observed. On the contrary, the initial inhibition of sperrnine-NI-acetyl-transferase (SAT) activity was followed by a progressive increase of this catabolic enzyme. These changes were related to modifications of cAMP concentrations. Our data may help clarify the mechanisms underlying the biphasic effect of PGE2, which ultimately leads to inibition of cell proliferation.     

Polyamine metabolism in cells infected with herpes simplex virus.

Ifection of LS cells with HSV-1 resulted in an inhibition of spermidine and spermine synthesis from putrescine, possibly through inhibition of host cell protein synthesis. The rate of putrescine uptake increased soon after infection, and later, polyamines were lost from the cells. Inhibition of spermidine and spermine synthesis by methylglyoxal bis (amidinohydrazone) did not affect virus replication.     

Polyamine metabolism in MRC-5 cells infected with human cytomegalovirus

The rate of putrescine uptake into MRC-5 cells increased markedly following infection with human cytomegalovirus (HCMV). Enhanced incorporation occurred immediately after infection and the highest levels were attained following the production of infectious, progeny virus. Parallel kinetic changes in the utilization of radio-labelled putrescine were shown by the amounts of spermidine and spermine recovered from infected cells as radioactive derivatives. A temporal correlation was found between these changes in polyamine metabolism and the synthesis of virus DNA. Methylglyoxalbis(guanylhydrazone), an inhibitor of spermidine and spermine synthesis, did not affect virus replication if HCMV-infected cells were exposed to the inhibitor after completion of the eclipse phase of the virus growth cycle. These results show that polyamine metabolism is required only during the initial stages of HCMV replication.     

Glycogen metabolism in Schistosoma mansoni worms after their isolation from the host

Adult Schistosoma mansoni worms rapidly degrade their endogenous glycogen stores immediately after isolation from the host. In NCTC 109 or in a diphasic culture medium the glycogen levels slowly recovered again after the initial decrease. The rapid degradation of glycogen could be prevented, even in a simple salt medium, if 100 mM glucose and 1% bovine serum albumin were present. Incubations with 14C-labelled glucose under different conditions revealed that the degradation of glycogen was induced by the limited catabolism of external glucose. Conditions are described which induce glycogen degradation or resynthesis by S. mansoni. The physiological function of the glycogen stores is probably to provide substrate during periods of insufficient supply of external glucose. It is speculated that such periods occur when the worm pair moves into the small mesenteric veins of the host. This hypothesis explains the remarkable wandering behaviour of the parasite in the mesenteric veins, since the schistosomes would have to return to larger vessels when their endogenous glycogen stores are exhausted.     

Polyamine metabolism regulation by histamine and other biogenic amines in Ehrlich carcinoma cells

Polyamines feed-back regulate ornithine decarboxylase activity (ODC). Histamine, serotonin and cadaverine (amino acid decarboxylase products) somehow mimic the role known for polyamines. Serotonin, tryptamine, histamine and its analog chlorpheniramine inhibited the ODC induction caused by 0.5 mM ornithine. The presence of these diamines in the perfusion medium at 55 M reduced the intracellular concentrations of ornithine. Results on intracellular concentrations of histamine, cadaverine and putrescine after different perifusion conditions suggest that a metabolic interplay could be involved between these biogenic amines, since the cell accumulation of one of them led to an increase in the intracellular concentrations of the others.     

Polyamine biosynthesis in trichomonads

Trichomonas vaginalis, Tritrichomonas foetus and Trichomitus batrachorum grown in modified Diamond's medium all had high concentrations of putrescine and lower concentrations of spermidine and spermine. Ornithine decarboxylase (ODC; EC 4.1.1.17) was detectable in all three species although at significantly different levels. Trichomonas vaginalis had the highest activity (typically around 1.85 nmol min-1 (mg protein)-1), Trichomitus batrachorum the lowest (0.11 nmol min-1 (mg protein)-1). The Trichomonas vaginalis ODC had an apparent Mr of 230 000 and was severely inhibited by alpha-difluoromethylornithine (DFMO). S-Adenosyl-methionine decarboxylase (EC 4.1.1.50) could not be detected in T. batrachorum but was present in the other two species. Arginine decarboxylase was apparently absent from all three. All three trichomonad species were able to accumulate spermidine and putrescine from the medium. When T. vaginalis was grown in the presence of DFMO (4 mM), which had little effect on parasite growth, ODC activity was reduced by over 99% and the polyamine content was altered; putrescine concentrations were decreased, those of spermidine and spermine remained the same or were raised. DFMO-treated cells accumulated more exogenous putrescine than untreated control cells. The results suggest that the lack of effect of DFMO on T. vaginalis in culture was due to the parasite being able to accumulate polyamines from the growth medium. It appears, therefore, that testing DFMO and similar compounds in axenic trichomonad cultures may well not give a true indication of their effectiveness in vivo where sources of exogenous polyamines may not be available.     

Polyamine N-acetyltransferase in Leishmania amazonensis

 N-Acetyltransferase, which is suggested to be responsible for the production of N ¹-acetylspermidine in Leishmania amazonensis and to be involved in the process of inactivation and degradation of excessive polyamines, was partially purified and characterized. Among the substrates tested, sym-norspermidine, sym-norspermine, and 1,3-diaminopropane had the highest reaction rates, but the naturally occurring polyamines spermine and spermidine were also acetylated at considerable rates, whereas putrescine was a poor substrate. The Michaelis constants (K _m values) for spermine and spermidine were 0.66 and 3.3 mM, respectively. The K_m value for acetylcoenzyme A (acetyl-CoA) was determined to be 34 μM. CoA inhibited the reaction in a competitive manner; the inhibition constant was 5 μM. The enzyme showed an apparent relative molecular mass of 35,000. Received: 16 November 1995 / Accepted: 10 January 1996     

Polyamine levels in gynecologic malignancies

Polyamines are closely related to many aspects of cell growth. Since increased amounts of polyamines in the urine of human cancer patients were reported in 1971, polyamines have been studied from the standpoint of tumor markers. In this study, polyamines in erythrocytes, plasma and urine were determined in 42 controls and 105 patients with gynecologic malignant tumors. The changes in polyamine levels were investigated before and after treatment. With advances in the stage of uterine cervical cancer, the frequency of abnormal levels of polyamines (concentrations greater than two standard deviations above the mean control level) became greater, and reached nearly 80% in recurrent and ovarian cancer. In the early stage of cancer, the diagnostic value was low. Comparison with carcinoembryonic antigen (CEA) was also performed. The polyamines lack specificity for malignant diseases, but they can be used to some extent as a tumor marker in the gynecologic field.     

Mononuclear and multinuclear macrophages in filarial infections

Filarial infections commonly involve chronic tissue responses to these complex and resiliant organisms. These responses, which occur with a number of the parasitic stages of filariae, involve macrophages, and these cells appear to be important in immunologically induced destruction and removal of these important parasites of man and animals. Details of their presence and experimental induction as well as their distinction into a number of morphological types, including multinuclear (giant cell) forms, is described in this communication. The ability of these various forms to function in phagocytic and immunologically mediated adherence assays is also described.     

多胺的合成代谢与肿瘤治疗

多胺合成代谢关键酶鸟氨酸脱羧酶(ODC)和S-腺苷甲硫氨酸脱羧酶(Ado Met DC)与肿瘤的发生和转移密切相关。现有的ODC和Ado Met DC的抑制剂在临床实验中毒不良反应大或疗效不佳,将抑制剂和其他药物联用或通过计算机与实验相结合的方式开发小分子抑制剂有望为肿瘤治疗提供新的思路。     

Immunopathogenesis of lymphatic filarial disease

Although two thirds of the 120 million people infected with lymph-dwelling filarial parasites have subclinical infections, ～40 million have lymphedema and/or other pathologic manifestations including hydroceles (and other forms of urogenital disease), episodic adenolymphangitis, tropical pulmonary eosinophilia, lymphedema, and (in its most severe form) elephantiasis. Adult filarial worms reside in the lymphatics and lymph nodes and induce changes that result in dilatation of lymphatics and thickening of the lymphatic vessel walls. Progressive lymphatic damage and pathology results from the summation of the effect of tissue alterations induced by both living and nonliving adult parasites, the host inflammatory response to the parasites and their secreted antigens, the host inflammatory response to the endosymbiont Wolbachia, and those seen as a consequence of secondary bacterial or fungal infections. Inflammatory damage induced by filarial parasites appears to be multifactorial, with endogenous parasite products, Wolbachia, and host immunity all playing important roles. This review will initially examine the prototypical immune responses engendered by the parasite and delineate the regulatory mechanisms elicited to prevent immune-mediated pathology. This will be followed by a discussion of the proposed mechanisms underlying pathogenesis, with the central theme being that pathogenesis is a two-step process—the first initiated by the parasite and host innate immune system and the second propagated mainly by the host's adaptive immune system and by other factors (including secondary infections).     

Polyamine uptake systems in Escherichia coli.

The polyamine content of cells is regulated by biosynthesis, degradation, and transport. In Escherichia coli, the genes for three different polyamine transport systems have been cloned and characterized. Two uptake systems (putrescine-specific and spermidine-preferential) are ABC transporters, each consisting of a periplasmic substrate binding protein, two transmembrane proteins, and a membrane-associated ATPase. The third transport system, catalyzed by PotE, mediates both uptake and excretion of putrescine. In this article, the properties of the first two polyamine uptake systems are reviewed in detail.