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PubMedDate not supplied

Effects of suramin on polyamine metabolism in B16 murine melanoma cells.

Polyamines and their biosynthetic enzymes, such as ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), are crucial for normal and neoplastic cell growth and differentiation. Suramin inhibits the growth of several tumor cells by affecting various intracellular targets, but its effects on polyamines are not known. In this study, the effects of suramin on some parameters of polyamine metabolism in B16 melanoma cells were investigated in vitro. Suramin increased cellular ODC activity and ODC mRNA levels, whereas the drug was directly inhibitory to the enzyme. AdoMetDC was not affected. Cellular putrescine levels were enhanced by suramin, whereas spermidine and spermine pools were unaltered. Cells cultured in the presence of suramin showed decreased cellular polyamine transport, but no direct inhibitory effect on the polyamine transporter could be found. Fluorescence spectroscopy demonstrated a direct interaction between suramin and spermine. It may be concluded that suramin affects polyamine metabolism, and that its effects in some respects are opposite to those of alpha-difluoromethylomithine (DFMO), a specific inhibitor of ODC.

Adenosylmethionine Decarboxylase↗
PubMed1994

Effect of eliprodil, an NMDA receptor antagonist acting at the polyamine modulatory site, on local cerebral glucose use in the rat in the rat brain.

The present investigation examined the effect of eliprodil, an atypical NMDA receptor antagonist that acts at the polyamine modulatory site, on local cerebral glucose utilization using the quantitative autoradiographic 2-[14C]deoxyglucose method in the conscious rat. Eliprodil, at doses of 3, 10 and 30 mg/kg i.p., did not increase cerebral glucose use in any of the 82 different brain regions studied. However, in some of the regions examined, local cerebral glucose utilization was slightly reduced, the most pronounced decreases being measured in some extrapyramidal, sensorimotor and limbic areas (dentate gyrus, septum, lateral habenula, amygdala). This decrease in glucose utilization was dose-dependent: no significant change was noted after 3 mg/kg i.p. of eliprodil, while 18 (at 10 mg/kg, i.p.) and 29 (at 30 mg/kg, i.p.) regions displayed a moderate (20-25%) though significant decrease in glucose use. These data demonstrate that the pattern of alterations in glucose use produced by eliprodil is different from that induced by NMDA channel blockers or competitive NMDA receptor antagonists. The fact that blockade of the polyamine modulatory site is not associated with an activation of specific limbic circuits may explain why, at neuroprotective doses, eliprodil is devoid of those unwanted side effects (including intrinsic neurotoxicity on cortical neurons) associated with NMDA channel blockers.

Animals↗
PubMed2001

Regulation of cellular polyamines by antizyme.

Proteins that are degraded by the proteasome are first modified by a set of enzymes that attach multiple copies of ubiquitin to substrate lysines, but a tiny minority, including the polyamine-synthesizing enzyme ornithine decarboxylase, is handled differently. This enzyme is targeted for destruction by another protein--antizyme. Why does ornithine decarboxylase have its own dedicated destruction mechanism, how does it work, and is it the only protein to be targeted to the proteasome in this way?

Animals↗
PubMed1994

MGBG: teaching an old drug new tricks.

Methylglyoxalbisguanylhydrazone or MGBG is an agent with a unique mechanism of action (polyamine biosynthesis inhibition). MGBG was discarded in the 1960s because of severe mucositis and other toxicities. New clinical trials in the late 1970s and early 1980s utilized weekly administration and indicated MGBG had significant activity in patients with chemotherapy-refractory Hodgkin's and non-Hodgkin's lymphoma. In addition, some activity was noted in patients with head and neck, prostate, esophageal, and endometrial cancer. The toxicities on the weekly schedule were minimal and no myelosuppression was noted. Based on MGBG's spectrum of antitumor activity and its activity in severely debilitated patients, we hypothesize that MGBG may have greater antitumor activity in patients who are malnourished (possibly based on polyamine depletion). MGBG is a good candidate for treatment of AIDS-associated NHL because it has proven activity in patients with NHL which is not associated with AIDS, crosses the blood brain barrier, is non-myelosuppressive, and appears to work in patients with inanition (no polyamines available to reverse MGBG's antitumor effects). Clinical trials are ongoing to determine the activity of MGBG in AIDS-associated NHL and other diseases. Based on encouraging initial results, it appears MGBG may become part of our therapeutic armamentarium.

Adult↗
PubMed2004

Cisplatin up-regulates the in vivo biosynthesis and degradation of renal polyamines and c-Myc expression.

Time-dependent changes in polyamine metabolism and c-Myc expression are reported in kidney of mice treated with cisplatin, a widely used anticancer drug. We show that cisplatin significantly induces the expression of two enzymes critical to proper homeostasis of cellular polyamines, ornithine decarboxylase (ODC) and spermidine/spermine N1-acetyltransferase (SSAT). We also document the cross-talk between signalling pathway(s) induced by cisplatin injury to renal tubules and the testosterone/androgen receptor pathway. Their interaction results in a decrease in testosterone-induced ODC activity and ODC mRNA level, and in differential modulation of SSAT expression. Moreover, cisplatin and antifolate CB 3717, another nephrotoxic drug examined, severalfold up-regulate expression of c-Myc mRNA, albeit with different kinetics. However, cisplatin, contrary to CB 3717, does not induce renal hepatocyte growth factor (HGF)/c-Met expression being without effect on HGF mRNA level and significantly down-regulating c-Met transmembrane receptor message. In conclusion, these in vivo studies document significant cisplatin-induced modulation of polyamine biosynthesis/degradation and up-regulation of c-Myc expression, and suggest that c-Myc transcription factor is involved in the induction of ODC in kidney injured with antifolate, but not with cisplatin.

Acetyltransferases↗
PubMed2003

Inhibition of human colon carcinoma cell growth by ammonia: a non-cytotoxic process associated with polyamine synthesis reduction.

Ammonia, produced by bacterial degradation of unabsorbed and endogenous nitrogenous compounds, is found to be present at millimolar concentrations in the colon lumen. From in vivo animal experiments, this metabolite has been shown to alter colonic epithelial cell morphology and to increase compensatory cell proliferation when present in excess. In this in vitro study, using the human colon adenocarcinoma HT-29 Glc(-/+) cell line treated with increasing doses of NH(4)Cl, we found that 20 mM NH(4)Cl, a concentration close to that found in the large intestine lumen, was able to increase the volume of vacuolar lysosomes and to repress HT-29 Glc(-/+) cell proliferation. This growth-inhibitory effect was not correlated with decrease of cell viability, with modification of cell differentiation and change of the cell distribution in the different cell cycle phases, thus indicating a proportional slowdown in all cell cycle phases. In contrast to what is found in healthy colonocytes, ammonia was not metabolized by HT-29 cells into carbamoyl-phosphate (carbamoyl-P) and citrulline, indicating that ammonia was likely acting on cells by itself. This agent was shown to markedly reduce cellular ornithine decarboxylase (ODC) activity resulting in a threefold decrease in the capacity of HT-29 cells to synthetize polyamines, these latter metabolites being strictly necessary for cell growth. The unexpected finding that ammonia is acting as an antimitotic agent against tumoral HT-29 colonic cells may be related to the inability of these cells to metabolize this compound.

Ammonia↗
PubMed1994

Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps.

BACKGROUND: alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of carcinogenesis in experimental animal models. In these animal models, DFMO has been especially active in preventing carcinogen-induced epithelial cancers, including those of the skin, colon, breast, and urinary bladder. Although DFMO is known to exert its diverse biological effects by suppressing intracellular pools of the polyamines putrescine and spermidine, the precise mechanism by which polyamine depletion, induced by DFMO, suppresses carcinogenesis is unknown. PURPOSE: The specific aim of our study was to determine the lowest dose of DFMO that would deplete target tissue (colorectal mucosa) levels of these polyamines in humans who had undergone prior removal of colon polyps while producing minimal toxic effects. METHODS: A dose de-escalation chemoprevention trial of DFMO was conducted in 111 patients (36 female and 75 male) who were in generally good health, aged 39-79, and who had undergone colonoscopy for surgical removal of an adenomatous colon polyp greater than 3 mm within 5 years prior to entering the study. Groups of patients (12-20 patients per group) were orally treated with single, daily doses of DFMO ranging from 3.0 to 0.1 g/m2 for 4 weeks (28 days). Prior to initiation of DFMO treatment and at the end of treatment, six colorectal biopsy specimens were collected from each patient, along with serum samples. All biopsies were performed between 9 AM and noon to avoid possible effects of diurnal variations in laboratory end points. Samples for analysis of plasma DFMO levels were also collected during this time period on the day after the last day of drug administration. RESULTS: DFMO caused a decrease in both putrescine content and the ratio of spermidine to spermine for all dose groups down to 0.25 g/m2. Both putrescine content and the ratio of spermidine to spermine and changes in these parameters as a function of DFMO treatment decreased as a function of donor age. None of the 30 patients receiving either 0.25 or 0.5 g/m2 experienced any clinical ototoxicity in this trial. CONCLUSIONS: DFMO is both safe and effective in reducing colorectal mucosal polyamine contents when it is administered orally to patients at doses as low as 0.25 g/m2 for 28 days. No ototoxicity was observed at doses up to twice this amount. IMPLICATIONS: If DFMO is also found to be effective in suppressing polyamine contents in other target tissues, it may be useful in preventing a wide range of human epithelial cancers, including those of the prostate and breast.

Administration, Oral↗
PubMed1995

Dissimilar effect of the carcinogenic agent azaserine on pancreatic and hepatic polyamine metabolism in rats.

The present study was designed to investigate the effects of the carcinogenic agent azaserine on the induction of pancreatic and hepatic polyamine metabolism in rats. One single injection of 30 mg azaserine/kg body weight i.p. is known to induce adenoma and subsequently carcinoma, predominantly in the pancreas, after several months. Male Lewis rats were treated with either azaserine (30 mg/kg body weight i.p.) or saline and 5-10 animals per group were sacrificed 2, 6, 9, 12, 18, 24, and 48 h later. Furthermore, animals were simultaneously treated with the ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) or the polyamine oxidase inhibitor MDL 72527 and killed 6 and 12 h after azaserine injection. The azaserine-induced significant increase in pancreatic putrescine concentrations was accompanied by an increase in spermidine/spermine N1-acetyltransferase but unchanged ODC and was significantly inhibited by N, N'-bis(2,3-butadienyl)putrescine (MDL 72527) but not by DFMO. S-Adenosylmethionine decarboxylase (SAM-DC) activity was significantly decreased in the pancreata of azaserine-treated animals compared to controls. In contrast, the azaserine-induced significant increase in hepatic putrescine was lower and transient, was accompanied by an increase in ODC and SAM-DC, and was completely inhibited by simultaneous DFMO treatment but not by MDL 72527. These data show completely different patterns of activation of polyamine metabolism in the pancreas and in the liver: Azaserine treatment forms putrescine in the liver by de novo synthesis via ODC only, while azaserine-induced pancreatic putrescine is exclusively produced by the interconversion pathway via oxidation of N1-acetylspermidine.

Animals↗
PubMed2005

Suppression and regression of choroidal neovascularization by polyamine analogues.

PURPOSE: Polyamine analogues inhibit tumor growth in vitro and in vivo, and oligoamines with a chain length of 10, 12, or 14 are particularly potent. This study was conducted to investigate the effect of the decamines CGC-11144 and CGC-11150 in a mouse model of choroidal neovascularization (CNV). METHODS: Mice with laser-induced rupture of Bruch's membrane were given intraperitoneal, intravitreous, or periocular injection of CGC-11144, CGC-11150, or vehicle, and after 14 days, they were perfused with fluorescein-labeled dextran, and the area of CNV was measured on choroidal flatmounts by image analysis. In some groups of mice, treatments were started 7 days after rupture of Bruch's membrane to determine the effect of the agent on established CNV. Electroretinograms (ERGs) were performed to assess the effects on retinal function, and histopathology was used to evaluate retinal structure. RESULTS: Intraperitoneal injection of 10 or 20 mg/kg CGC-11144 or CGC-11150 resulted in small but significant reductions in the area of CNV. Intravitreous injection of 20 microg CGC-11144 or CGC-11150 on days 0 and 7 after rupture of Bruch's membrane resulted in a approximately 40% reduction in the area of CNV, with a similar reduction after periocular injections of 0.2 mg CGC-11144 three times a week for 2 weeks. Both intravitreous and periocular delivery of CGC-11144 also caused significant regression of established CNV. Within 2 days of periocular injection of CGC-11144, there was apoptosis in CNV lesions, but not in normal blood vessels or other retinal cells. Periocular injections of d,l-alpha-difluoromethyl-ornithine (DFMO), which decreases polyamine levels by a different mechanism, also inhibited CNV. There was no decline in ERG amplitudes or abnormal retinal morphology after daily injections of 0.2 mg CGC-11144 for 2 weeks, but a single intravitreous injection compromised retinal structure and function. CONCLUSIONS: Periocular delivery of the polyamine analogues may be a useful approach for the treatment of CNV.

Animals↗
PubMed1995

[Polyamines and cell growth: specific aspects in Amoeba proteus and in certain cancer cell lines].

The differences between the metabolic schemes of polyamines can be the starting point to investigate the discovery of new antiparasitic or anticancer drugs which would be cell type specific. The studies, which were undertaken with the P388 cancer cells and Amoeba proteus, have shown that the pool of polyamine was very different in both cell types. Moreover, the cytotoxicity of putrescine, spermidine, spermine and 1-3 diaminopropane was found to be dependent of the activity of cell enzymes which could play a role to control cell proliferation by producing toxic metabolites.

Amoeba↗
PubMed2003

Structure and expression of spermidine synthase genes in apple: two cDNAs are spatially and developmentally regulated through alternative splicing.

Three cDNAs (MdSPDS1, 2a and 2b) encoding spermidine synthase (SPDS), a key enzyme in the polyamine biosynthesis, have been cloned from apple [Malus sylvestris (L.) Mill. var. domestica (Borkh.) Mansf.]. The deduced amino acid sequences of their protein products share 76-83% identity with SPDSs of other higher plants. A comparison of the sequences of the three cDNAs and of the two corresponding genomic DNA fragments (SPDS1 and SPDS2) indicated that MdSPDS1 was transcribed from the SPDS1 sequence, whereas MdSPDS2a and MdSPDS2b were both derived from SPDS2 by alternative splicing. To learn more about the physiological roles of MdSPDS1, MdSPDS2a and MdSPDS2b, Northern analyses were carried out, together with measurements of polyamine content. Levels of both MdSPDS1 and MdSPD2a were higher in young leaves than in mature leaves and shoots. In fruits, mRNA levels were nearly as high as in young leaves and remained high during fruit development. By RT-PCR, MdSPDS2b transcripts were detected in mature leaves and shoots, but not in young leaves and fruits. These results indicate that MdSPDS2a and MdSPDS2b are differentially regulated in a tissue- and developmentally specific manner. The content of free polyamines in mesocarp tissues was measured at five stages of fruit development. At all stages, spermidine (Spd) was the predominant form of polyamine. The level of Spd was high at the early growth stage and declined to about 90% during later developmental stages. The possible regulation of SPDS expression during apple fruit development is discussed.

Alternative Splicing↗
PubMed1998

Partial contribution of polyamines to the relaxant effect of 17 alpha-estradiol in rat uterine smooth muscle.

1. The effects of 17 alpha-estradiol on KCl (60 mM), CaCl2 (30 microM to 10 mM) and vanadate (0.3 mM)-induced contractions in rat uterus have been assayed. Furthermore, the effect of 17 alpha-estradiol on calmodulin-stimulated cAMP-phosphodiesterase activity was also studied. 2. 17 alpha-estradiol relaxed the tonic contraction induced by KCl (60 mM) in a concentration-dependent way (IC50, 8.3 +/- 0.7 microM), and CaCl2 (0.1 to 10 mM) counteracted it. 3. CaCl2 (30 microM to 10 mM) produced concentration-dependent contraction of rat uterus in a calcium-free medium supplemented with 60 mM of KCl (EC50: 0.2 +/- 0.01 mM). 17 alpha-estradiol (8 microM) antagonized the contraction induced by CaCl2, increasing the EC50 value up to 0.7 +/- 0.1 mM (P < 0.01). 4. 17 alpha-estradiol (0.1 to 1 mM) relaxed in a concentration-dependent way the tonic contraction induced by vanadate in rat uterus incubated in a calcium-free medium and EDTA supplemented. The maximal relaxation achieved with 1 mM of 17 alpha-estradiol was 52.2 +/- 2.8%. 5. 17 alpha-estradiol (1 to 100 microM) did not modify the basal activity of cAMP-phosphodiesterase but inhibited the calcium plus calmodulin stimulated activity. The maximal inhibition achieved was 43 +/- 5.4%. 6. The relaxing effect of 17 alpha-estradiol on KCl (60 mM)-induced tonic contraction was unmodified with the antioestrogen tamoxifen (0.1 and 1 microM), the inhibitor of tirosine kinase (genistein, 10 microM) and the cAMP-dependent protein kinase inhibitor (Rp-adenosine 3',5'-monophosphothioate, triethylamine salt, 100 microM). However, the effect was antagonized with the inhibitor of transcription (actinomycin D, 5 micrograms/ml,), the inhibitor of protein synthesis (cycloheximide, 10 and 100 micrograms/ml), and the inhibitor of ornithine decarboxilase (alpha-difluoromethyl-ornithine, 10 mM). 7. Our results suggest that polyamines contribute to the relaxant effect of 17 alpha-estradiol in rat uterine smooth muscle behaving, presumably, as mediators of the transcriptional component involved in the effect of 17 alpha-estradiol.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Effect of polyamines on mitochondrial F1-ATPase catalyzed reactions.

The effect of polyamines on F1-ATPase catalyzed reactions has been studied through the use of submitochondrial particles and F1-ATPase. ATP degradation catalyzed by submitochondrial particles and F1-ATPase was inhibited by spermine and spermidine. Spermine's inhibition was much greater than spermidine's effect. In contrast, P1-ATP exchange and succinate dependent ATP synthesis catalyzed by submitochondrial particles were both stimulated by spermine. The inhibition of ATPase activity by polyamines probably occurs through polyamine's replacement of Mg2+ on ATP, for the following reasons. (a) The ATPase activity inhibited by spermine was partially recovered when Mg2+ was added. (b) Spermine bound to ATP and phospholipids but not to F1-ATPase; yet spermine inhibited the ATPase reaction catalyzed by F1-ATPase, a protein free of phospholipid. (c) The binding of spermine to ATP was inhibited by Mg2+. The ATP content in polyamine-deficient cells definitely was lower than that in normal cells. On the basis of these results, the possible role of spermine in keeping the ATP concentration at a high level is discussed.

Adenosine Diphosphate↗
PubMed1995

Determination of amounts of polyamines excreted in urine: demonstration of N1,N8-diacetylspermidine and N1,N12-diacetylspermine as components commonly occurring in normal human urine.

An analytical system developed for fractionating free and monoacetylated polyamines [Hiramatsu, K. et al. (1994) J. Biochem. 115, 584-589] was proved useful also in detecting diacetylpolyamines, namely N1,N8-diacetylspermidine (diAcSpd) and N1,N12-diacetylspermine (diAcSpm). Detection limits were 0.9 and 0.6 pmol (S/N = 5) for diAcSpd and diAcSpm, respectively. Analytical recovery and within-run variation were also satisfactory. Human urine samples were found to contain diAcSpd and diAcSpm. These polyamines were identified on the basis of the following observations: (i) their retention times were coincident with those of authentic samples; (ii) they were deacetylated to N8-acetylspermidine and monoacetyl- and free spermine, respectively, by acetylpolyamine amidohydrolase; and (iii) they were practically inert to direct oxidation by bacterial polyamine oxidase as were authentic samples. The amounts of eleven polyamine species including diAcSpd and diAcSpm in urine samples from 52 healthy persons were determined. Mean values for the major polyamine components were consistent with those reported by others. Although the amounts of diAcSpd and diAcSpm were very small, comprising only 1.4 and 0.46% of total polyamines, respectively, these two compounds were found to be always present in healthy human urine as regular constituents. Moreover, variation in their content among individuals was small, suggesting that excretion of these components in urine is strictly regulated.

Biogenic Polyamines↗
PubMed2006

Liver I/R injury is improved by the arginase inhibitor, N(omega)-hydroxy-nor-L-arginine (nor-NOHA).

Liver ischemia-reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. The purpose of this study was to determine whether arginase inhibition with N(omega)-hydroxy-nor-l-arginine (nor-NOHA) would increase circulating arginine levels and decrease hepatic damage during liver I/R injury. The effects of nor-NOHA were initially tested in normal animals to determine in vivo toxicity. In the second series of experiments, orthotopic syngeneic liver transplantation (OLT) was performed after 18 h of cold ischemia time in Lewis rats. Animals were given nor-NOHA (100 mg/kg) or saline before and after graft reperfusion. In normal animals treated with nor-NOHA, there were no histopathological changes to organs, liver enzymes, serum creatinine, or body weight. In the OLT model, animals treated with saline exhibited markedly elevated serum transaminases and circulating arginase protein levels. Nor-NOHA administration blunted the increase in serum arginase activity by 80% and preserved serum arginine levels at 3 h after OLT. Nor-NOHA treatment reduced post-OLT serum liver enzyme release by 50%. Liver histology (degree of necrosis) in nor-NOHA-treated animals was markedly improved compared with the saline-treated group. Furthermore, use of the arginase inhibitor nor-NOHA did not influence polyamine synthesis owing to the decrease in ornithine levels. Arginase blockade represents a potentially novel strategy to combat hepatic I/R injury associated with liver transplantation.

Alanine Transaminase↗
PubMed2006

Polyamine-mediated reduction in human airway epithelial migration in response to wounding is PGE2 dependent through decreases in COX-2 and cPLA2 protein levels.

Both ornithine decarboxylase inhibition to deplete polyamines and cyclooxygenase inhibition diminish the migration response to injury of human airway epithelial cells in tissue culture monolayers by approximately 75%. Restoration of normal migration responses is achieved in the polyamine depleted system either by exogenous reconstitution of polyamines or the addition of prostaglandin E(2) (PGE(2)). However, only PGE(2) was able to restore migration in the cyclooxygenase-inhibited systems. Western blot for cyclooxygenase-2 and cytosolic phospholipase A(2) protein levels and ELISAs for PGE(2) secretion demonstrate dramatic increases over 24-48 h after monolayer wounding. These increases are completely abolished by polyamine depletion or cyclooxygenase inhibition. We conclude that polyamine inhibition decreases cellular migration in response to injury in airway epithelial cells at least in part through inhibiting normal PGE(2) production in response to injury. This may be brought about by decreases in cytosolic phospholipase A(2) and cyclooxygenase-2 protein levels.

Biogenic Polyamines↗
PubMed1989

Beneficial effects of a polyamine biosynthesis inhibitor on lupus in MRL-lpr/lpr mice.

Difluoromethylornithine (DFMO), an experimental drug that inactivates ornithine decarboxylase and thus reduces the production of polyamines has a beneficial effect on the mean survival time and the clinical and laboratory manifestations of murine lupus in female MRL-lpr/lpr mice. DFMO-treated mice showed a 29% increase in the mean survival time compared with age- and sex-matched control mice of the same strain. Lymphadenopathy was evident in untreated mice at 14 weeks of age, but was delayed until 19 weeks of age in DFMO-treated mice. In addition, the sera of DFMO-treated mice contained a significantly lower concentration of anti-DNA antibodies compared with untreated mice. These results open the possibility of development of a new class of therapeutic agents based on polyamine biosynthesis inhibitors for the treatment of human autoimmune disease. Possible mechanisms for the action of DFMO include its inhibitory action on cell proliferation as well as its ability to prevent DNA from assuming an immunogenic left-handed Z-DNA conformation.

Animals↗
PubMed2004

L-arginine metabolism during interaction of Trypanosoma cruzi with host cells.

Trypanosoma cruzi invades a diversity of nucleated cells in the mammalian host. Macrophages are among the first cells to be parasitized and, after activation by inflammatory stimuli, they participate in the control of infection. However, some parasites manage to evade the immune response and establish a chronic infection in differentiated cells. L-arginine is located at the crossroads of divergent routes that produce metabolites, including nitric oxide and polyamines, which influence the outcome (i.e. resolution or progression) of infection. This article discusses the fate and actions of L-arginine-derived biomolecules formed both in the host and in the parasite during T. cruzi-host-cell interactions.

Animals↗